Skip to main content
NCBI home page
Frontiers in Pharmacology logoLink to Frontiers in Pharmacology
. 2022 Sep 13;13:1001861. doi: 10.3389/fphar.2022.1001861

The top 100 cited studies on bacterial persisters: A bibliometric analysis

Yuan Ju 1, Haiyue Long 2, Ping Zhao 1, Ping Xu 1, Luwei Sun 1, Yongqing Bao 1, Pingjing Yu 1,*, Yu Zhang 1,*
PMCID: PMC9513396  PMID: 36176451

Abstract

Background: Bacterial persisters are thought to be responsible for the recalcitrance and relapse of persistent infections, and they also lead to antibiotic treatment failure in clinics. In recent years, researches on bacterial persisters have attracted worldwide attention and the number of related publications is increasing. The purpose of this study was to better understand research trends on bacterial persisters by identifying and bibliometrics analyzing the top 100 cited publications in this field.

Methods: The Web of Science Core Collection was utilized to retrieve the highly cited publications on bacterial persisters, and these publications were cross-matched with Google Scholar and Scopus. The top 100 cited publications were identified after reviewing the full texts. The main information of each publication was extracted and analyzed using Excel, SPSS, and VOSviewer.

Results: The top 100 cited papers on bacterial persisters were published between 1997 and 2019. The citation frequency of each publication ranged from 147 to 1815 for the Web of Science Core Collection, 153 to 1883 for Scopus, and 207 to 2,986 for Google Scholar. Among the top 100 cited list, there were 64 original articles, 35 review articles, and 1 editorial material. These papers were published in 51 journals, and the Journal of Bacteriology was the most productive journal with 8 papers. A total of 14 countries made contributions to the top 100 cited publications, and 64 publications were from the United States. 15 institutions have published two or more papers and nearly 87% of them were from the United States. Kim Lewis from Northeastern University was the most influential author with 18 publications. Furthermore, keywords co-occurrence suggested that the main topics on bacterial persisters were mechanisms of persister formation or re-growth. Finally, “Microbiology” was the most frequent category in this field.

Conclusion: This study identified and analyzed the top 100 cited publications related to bacterial persisters. The results provided a general overview of bacterial persisters and might help researchers to better understand the classic studies, historical developments, and new findings in this field, thus providing ideas for further research.

Keywords: bacterial persisters, bibliometric analysis, top-cited, citation analysis, VOSviewer

Introduction

Persistent bacterial infections pose significant public health problems, which increase the treatment time and costs, as well as cause death of millions of people every year (Monack et al., 2004; Chen and Wen, 2011; Martinecz and Abel zur Wiesch, 2018). Persistent bacterial infections are related to recurrent and recalcitrant infectious diseases in clinics, like implant device-related infections, lung infections of cystic fibrosis patients, urinary tract infections, and tuberculous granulomas (Singh et al., 2000; Anderson et al., 2004; Mack et al., 2004; Monack et al., 2004; Fisher et al., 2017). There are great medical challenges in treating these chronic infectious diseases as they are hard to be eradicated by antibiotics. Both the host and bacterial factors are involved in the antibiotic treatment failure, including immunosuppression, immunosurveillance, antibiotic recalcitrance, and biofilms (Monack et al., 2004; Fisher et al., 2017). Besides, the presence of bacterial persisters has attracted more attention because of their important role in persistent infections (Zhang, 2014; Fisher et al., 2017). Bacterial persisters are a small fraction of non-growing bacteria that are tolerant to antibiotics, and have been shown to accelerate the emergence of antibiotic resistance and relate to the resistance of biofilms (Cohen et al., 2013; Levin-Reisman et al., 2017; Spoering and Lewis, 2001; den Bergh et al., 2017). Bacterial persisters were first observed by Gladys Hobby (Hobby et al., 1942). She found that a small number of bacteria could survive under intensive antibiotic treatments in the culture. Then, Joseph Bigger named this subpopulation “persisters” in 1944 (Bigger, 1944). Over the last few decades, researches on bacterial persisters have made significant progress. For example, several studies showed that epigenetic factors can promote the phenotypic switching between persisters and normal-state bacteria (Balaban et al., 2004; Dhar and McKinney, 2007; Helaine et al., 2014). However, a bibliometrics analysis on bacterial persisters that reflects these advances is still lacking.

The citation frequency of a publication usually reflects its’ academic impact and the level of interest of the research community in a particular field. Therefore, a high number of citations indicate the significant contributions of this paper in the field and the potential of the paper to trigger a new research direction (Van Noorden et al., 2014; Fardi et al., 2017). Analysis of the most cited publications, especially the top 100 cited publications, provides insight into the most significant achievements of past researches over the recent decades, and this information can then be used to guide future research (Godin, 2006; Arshad et al., 2020). Currently, numerous bibliometrics studies have been performed to determine the characteristics of the most cited publications in different fields, such as emergency medicine, psychiatry, medical informatics, immunology, orthodontics, and so on. (Tsai et al., 2006; Nadri et al., 2017; Tarazona et al., 2018; Jiang et al., 2019; Zhang et al., 2019; Zhang et al., 2021). Moreover, several studies have analyzed the top 100 cited publications in tuberculosis, pneumonia, and antibiotics (Zhang et al., 2017; Wang et al., 2019; Arshad et al., 2020). However, no bibliometrics analysis has been conducted to analyze the most cited publications in the field of bacterial persisters. Hence, this study aimed to identify the top 100 cited publications on bacterial persisters, and to provide a global perspective on the current status of bacterial persisters by analyzing the publication years, number of citations, characteristics of these papers, authors, countries, institutions, keywords and subject categories.

Materials and methods

Search strategy and inclusion criteria

Publications concerning bacterial persisters were searched from the Web of Science Core Collection (WosCC) database on 23 June 2022. The search strategy was as follows: TS (Topics) = (persister$ OR “persistent bacteri*” OR “antibiotic persisten*” OR “antibiotic toleran*”). No restrictions on country, publication year, and language were implemented on the investigation. The search results were sorted based on the citation frequency and two authors screened the full texts to identify the top 100 cited papers on bacterial persisters. The citation counts of these papers were cross-matched with Scopus and Google Scholar. Only publications focusing on bacterial persisters were included in the bibliometric analysis, while publications that mentioned persisters in passing were excluded. Disagreements were resolved by consensus-based discussion.

Data extraction

The following information of each publication was extracted from the WoS database: authors, title, journal, publication year, number of citations, country, institution, language, type of article, keywords, and subject categories. The impact factors (IFs) of the journals were manually supplemented from the Journal Citation Report (JCR) (Clarivate Analytics, Philadelphia, United States, available from https://jcr.clarivate.com/). For publications with two or more authors, the first-ranked author was identified as the first author, and the last-ranked author was identified as the last author. The counting of institution or country was based on the institution or country of the first author. For first authors with more than one institution or country, the first institution and country were used as country of origin. Similarly, the first category was selected for publication with more than one subject categories in the WoS database.

Statistical analysis

Statistical analyses of descriptive data were performed using Microsoft Excel 2010 and IBM SPSS Statistic 26.0. The Spearman rank test was utilized to analyze the correlation between variables among the age of publications, citation frequency, and IFs. The p value < 0.05 was defined as statistically significant. The VOSviewer 1.6.17 (Leiden University, the Netherlands, available from https://www.vosviewer.com/) (van Eck and Waltman, 2010; van Eck and Waltman, 2017) was applied to map the co-occurrence network of keywords. Keywords, which appeared more than two times in the top 100 cited publications, were presented in the co-occurrence network. In the network, each circle represented a keyword and the size of the circle represented the occurrence time of the keyword. Circles in the same color represented that these keywords were included in the same cluster. The circles were connected if they appeared in the same publication and the thickness of the line represented the number of times they appeared together.

Results

Year of publications and citations analysis

The top 100 cited papers were published between 1997 by Domingue and Woody (1997) and 2019 by Pang et al. (2019) and Balaban et al. (2019), but no publication in 1998 was included (Figure 1). In addition, 2013 and 2014 were the most productive years with more than 10 publications. The total citations per year of these publications showed a continuous upward trend over time, with the highest citations of 4,180 in 2020 (Figure 1).

FIGURE 1.

FIGURE 1

Open in a new tab

The distribution of annual publications and citations.

The Top 100 cited publications on bacterial persisters along with their total citations in WoSCC, Scopus, and Google Scholar were listed in Table 1. These publications received a total of 33,638 citations in WosCC, 35,097 citations in Scopus, and 54,194 citations in Google Scholar. The citation frequency of each publication ranged from 147 to 1,815 (WoSCC), 153 to 1,883 (Scopus), and 207 to 2,986 (Google Scholar). There were only four publications that had citations more than 1,000 times in WoSCC and Scopus, but nine publications in Google Scholar. The most cited paper was published by Nathalie Q. Balaban et al. (2004) with citation frequency of 1815 (WoSCC), 1883 (Scopus), and 2,986 (Google Scholar), describing the phenotypic switch of bacterial persistence. Besides, the publication entitled “Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies” had the largest mean citations per year (n = 141 of WoSCC, n = 147 of Scopus, and n = 241 of Google Scholar), which was published by Zheng Pang et al.Pang et al. (2019) in Biotechnology Advances in 2019.

TABLE 1.

The top 100 cited studies on bacterial persisters with total citation in WoSCC, Scopus, and Google Scholar databases.

Total citations
Rank Title Journal Year WoS a ES b GS c IF d
1 Bacterial persistence as a phenotypic switch Science 2004 1,815 1,883 2,986 31.853
2 Persister cells, dormancy and infectious disease Nature Reviews Microbiology 2007 1,239 1,298 2,118 14.959
3 Persister Cells Annual Review of Microbiology 2010 1,237 1,275 2,048 12.415
4 Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase Nature 2000 1,032 1,081 1,607 25.814
5 Platforms for antibiotic discovery Nature Reviews Drug Discovery 2013 844 875 1,553 37.231
6 Mechanisms of antibiotic resistance in bacterial biofilms International Journal of Medical Microbiology 2002 783 840 1,450 2.403
7 Persister cells and tolerance to antimicrobials FEMS Microbiology Letters 2004 695 746 1,224 1.840
8 Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials Journal of Bacteriology 2001 618 656 1,103 3.984
9 Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli Journal of Bacteriology 2004 601 634 1,021 4.146
10 Distinguishing between resistance, tolerance and persistence to antibiotic treatment Nature Reviews Microbiology 2016 597 615 975 26.819
11 Metabolite-enabled eradication of bacterial persisters by aminoglycosides Nature 2011 564 592 815 36.280
12 Multidrug tolerance of biofilms and persister cells Current Topics in Microbiology and Immunology 2008 517 544 940 5.102
13 Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence Frontiers in Cellular and infection Microbiology 2017 508 507 836 3.520
14 Biofilm infections, their resilience to therapy and innovative treatment strategies Journal of Internal Medicine 2012 484 503 819 6.455
15 Foamy macrophages and the progression of the human tuberculosis granuloma Nature Immunology 2009 481 504 840 26.000
16 Ciprofloxacin Causes Persister Formation by Inducing the TisB toxin in Escherichia coli Plos Biology 2010 475 509 725 12.472
17 Antibiotic tolerance facilitates the evolution of resistance Science 2017 472 483 706 41.058
18 Silver Enhances Antibiotic Activity Against Gram-Negative Bacteria Science Translational Medicine 2013 458 451 656 14.414
19 Recent functional insights into the role of (p)ppGpp in bacterial physiology Nature Reviews Microbiology 2015 440 443 669 24.727
20 Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters Science 2014 427 448 626 33.611
21 Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies Biotechnology Advances 2019 423 440 722 10.744
22 Persisters: a distinct physiological state of E-coli BMC Microbiology 2006 421 436 698 2.896
23 Persistent bacterial infections and persister cells Nature Reviews Microbiology 2017 418 428 657 31.851
24 Activated ClpP kills persisters and eradicates a chronic biofilm infection Nature 2013 416 430 617 42.351
25 Molecular Mechanisms Underlying Bacterial Persisters Cell 2014 399 420 612 32.242
26 Toxin-antitoxin systems in bacterial growth arrest and persistence Nature Chemical Biology 2016 392 410 574 15.066
27 Mechanisms of bacterial persistence during stress and antibiotic exposure Science 2016 386 396 579 37.205
28 Bacterial persistence: A model of survival in changing environments Genetics 2005 384 392 650 4.289
29 The challenge of treating biofilm-associated bacterial infection Clinical Pharmacology & therapeutics 2007 381 406 656 8.033
30 Growth Rate-Dependent Global Effects on Gene Expression in Bacteria Cell 2009 375 400 663 31.152
31 Bacterial persistence by RNA endonucleases Proceedings of the National Academy of Sciences of the United States of America 2011 373 397 553 9.681
32 Microbial cell individuality and the underlying sources of heterogeneity Nature Reviews Microbiology 2006 367 385 576 15.845
33 Emergence of Pseudomonas aeruginosa Strains Producing High Levels of Persister Cells in Patients with Cystic Fibrosis Journal of Bacteriology 2010 361 381 577 3.726
34 Dynamic Persistence of Antibiotic-Stressed Mycobacteria Science 2013 342 364 515 31.477
35 Bacterial Toxin-Antitoxin Systems: More Than Selfish Entities? Plos Genetics 2009 339 374 654 9.532
36 Bacterial Persister Cell Formation and Dormancy Applied and Environmental Microbiology 2013 334 343 568 3.952
37 Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy Proceedings of the National Academy of Sciences of the United States of America 2009 324 347 542 9.432
38 Definitions and guidelines for research on antibiotic persistence Nature Reviews Microbiology 2019 324 339 514 34.209
39 Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria Molecular Microbiology 2008 317 347 512 5.213
40 Persister cells and the riddle of biofilm survival Biochemistry-Moscow 2005 311 316 650 0.858
41 Persister formation in Staphylococcus aureus is associated with ATP depletion Nature Microbiology 2016 303 310 417 N/A
42 Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum Plos Medicine 2008 294 229 442 12.185
43 SOS Response Induces Persistence to Fluoroquinolones in Escherichia coli Plos Genetics 2009 293 313 494 9.532
44 Toxins, Targets, and Triggers: An Overview of Toxin-Antitoxin Biology Molecular Cell 2018 292 301 419 14.548
45 Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations Nature 2014 284 296 448 41.456
46 Toxin-Antitoxin Systems Influence Biofilm and Persister Cell Formation and the General Stress Response Applied and Environmental Microbiology 2011 284 300 435 3.829
47 Signaling-mediated bacterial persister formation Nature Chemical Biology 2012 278 294 417 12.948
48 A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen Plos One 2009 277 294 423 4.351
49 Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis Molecular Microbiology 2003 268 274 423 5.563
50 Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies Journal of Medical Microbiology 2011 268 274 432 2.502
51 Emergence of vancomycin tolerance in Streptococcus pneumoniae Nature 1999 267 306 461 29.491
52 Structure-Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis Journal of Medicinal Chemistry 2009 265 265 324 4.802
53 Microbial Persistence and the Road to Drug Resistance Cell Host and Microbe 2013 261 285 445 12.194
54 Characterization and Transcriptome Analysis of Mycobacterium tuberculosis Persisters Mbio 2011 238 254 341 5.311
55 Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence Proceedings of the National Academy of Sciences of the United States of America 2010 238 244 365 9.771
56 Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB Science 2009 236 251 370 29.747
57 New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects Lancet infectious Diseases 2014 233 254 378 22.433
58 Metabolic Control of Persister Formation in Escherichia coli Molecular Cell 2013 224 235 339 14.464
59 ATP-Dependent Persister Formation in Escherichia coli Mbio 2017 220 224 287 6.689
60 Microbial phenotypic heterogeneity and antibiotic tolerance Current Opinion in Microbiology 2007 216 231 385 7.654
61 Toxin-antitoxin systems: why so many, what for? Current Opinion in Microbiology 2010 213 223 336 7.714
62 Toxin-antitoxin modules as bacterial metabolic stress managers Trends in Biochemical Sciences 2005 211 215 297 13.343
63 The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms Science Translational Medicine 2018 207 208 241 17.200
64 Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli Antimicrobial Agents and Chemotherapy 2008 204 214 337 4.716
65 Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells Molecular Cell 2016 202 205 303 14.714
66 A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS Nature Chemical Biology 2012 199 212 318 12.948
67 Arrested Protein Synthesis Increases Persister-Like Cell Formation Antimicrobial Agents and Chemotherapy 2013 198 203 276 4.451
68 A new class of synthetic retinoid antibiotics effective against bacterial persisters Nature 2018 191 196 238 43.070
69 Biofilms in periprosthetic orthopedic infections Future Microbiology 2014 187 187 294 4.275
70 Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response Virulence 2013 182 185 309 3.319
71 Phenotypic Variation of Salmonella in Host Tissues Delays Eradication by Antimicrobial Chemotherapy Cell 2014 181 191 251 32.242
72 Toxins Hha and CspD and small RNA regulator Hfq are involved in persister cell formation through MqsR in Escherichia coli Biochemical and Biophysical Research Communications 2010 168 174 253 2.595
73 A problem of persistence: still more questions than answers? Nature Reviews Microbiology 2013 168 177 266 23.317
74 Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity Plos Pathogens 2014 167 175 236 7.562
75 Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals Proceedings of the National Academy of Sciences of the United States of America 2012 166 177 247 9.737
76 Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis Antimicrobial Agents and Chemotherapy 2003 165 190 300 4.246
77 Role of Oxidative Stress in Persister Tolerance Antimicrobial Agents and Chemotherapy 2012 164 179 254 4.565
78 Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins Journal of Bacteriology 2006 163 172 261 3.993
79 Formation, physiology, ecology, evolution and clinical importance of bacterial persisters FEMS Microbiology Reviews 2017 163 168 254 11.392
80 Targeting Persisters for Tuberculosis Control Antimicrobial Agents and Chemotherapy 2012 163 163 270 4.565
81 Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: Effects on macromolecular synthesis and persister formation Journal of Bacteriology 2006 162 166 263 3.993
82 Role of persisters and small-colony variants in antibiotic resistance of planktonic and biofilm-associated Staphylococcus aureus: an in vitro study Journal of Medical Microbiology 2009 160 174 280 2.272
83 Phenotypic bistability in Escherichia coli’s central carbon metabolism Molecular Systems Biology 2014 158 164 248 10.872
84 Starvation, Together with the SOS Response, Mediates High Biofilm-Specific Tolerance to the Fluoroquinolone Ofloxacin Plos Genetics 2013 157 170 262 8.167
85 Multiple Toxin-Antitoxin Systems in Mycobacterium tuberculosis Toxins 2014 157 155 216 2.938
86 HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase Nature Communications 2013 156 166 229 10.742
87 Pseudomonas aeruginosa Increases Formation of Multidrug-Tolerant Persister Cells in Response to Quorum-Sensing Signaling Molecules Journal of Bacteriology 2010 155 176 272 3.726
88 Evaluation of short synthetic antimicrobial peptides for treatment of drug-resistant and intracellular Staphylococcus aureus Scientific Reports 2016 154 158 192 4.259
89 Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis Nature Communications 2014 154 168 217 11.470
90 PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli Antimicrobial Agents and Chemotherapy 2007 154 157 244 4.390
91 Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection Plos One 2012 153 156 242 3.730
92 Persister cells, the biofilm matrix and tolerance to metal cations in biofilm and planktonic Pseudomonas aeruginosa Environmental Microbiology 2005 153 162 246 4.559
93 Dormancy Is Not Necessary or Sufficient for Bacterial Persistence Antimicrobial Agents and Chemotherapy 2013 151 155 230 4.451
94 Bridging the gap between viable but non-culturable and antibiotic persistent bacteria Trends in Microbiology 2015 151 167 238 9.500
95 Biofilm-related disease Expert Review of Anti-infective therapy 2018 149 155 228 3.090
96 Letting Sleeping dos Lie: Does Dormancy Play a Role in Tuberculosis? Annual Review of Microbiology, Vol 64, 2010 2010 149 162 265 N/A
97 Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control Cell Chemical Biology 2017 148 156 201 5.592
98 Bacterial persistence and expression of disease Clinical Microbiology Reviews 1997 148 146 275 8.585
99 GlpD and PlsB participate in persister cell formation in Eschetichia coli Journal of Bacteriology 2006 147 145 237 3.993
100 Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli Journal of Bacteriology 2006 147 153 217 3.993
Open in a new tab
a

WoS represented WoSCC database;

b

ES represented Elsevier Scopus database.

c

SC represented Google Scholar database.

d

IF showed the IF of journal in the year of publication, and the N/A represented that the journal IF had not been assigned in the year of publication.

The Spearman rank test indicated that there was a statistically significant downward trend in the mean citations per year with the increase in publication age (r = −0.488, p < 0.001 of WoSCC; r = −0.489, p < 0.001 of Scopus; r = −0.422, p < 0.005 of Google Scholar) (Figure 2A, Supplementary Figures S1A, S1B). However, no significant relationship was observed between the age of publications and the number of total citations (p = 0.248 of WoSCC; p = 0.209 of Scopus; p = 0.018 of Google Scholar) (Figure 2B, Supplementary Figures S1C, S1D).

FIGURE 2.

FIGURE 2

Open in a new tab

The relationship among total citations, mean citations per year, and publication age in WoSCC database. (A) Association of total citations with publication year (r = −0.488, p < 0.001 =; (B) Association of mean citations per year with publication age (p = 0.248).

Characteristics of publications

The top 100 cited publications on bacterial persisters were all written in English. Among the publications, there were 64 original articles, 35 review articles, and one editorial material. The citation frequencies for each publication type were 20,287 (original articles), 13,183 (review articles), and 168 (editorial material). However, the type of review had the highest average citation count per paper (n = 377).

Overall, the top 100 cited papers on bacterial persisters were published in 51 journals (Table 2). The 2021 IFs of these journals ranged from 2.82 (FEMS Microbiology Letters) to 112.288 (Nature Reviews Drug Discovery), and 23 journals had 2021 IFs greater than 10. Journal of Bacteriology published the greatest number of papers (eight papers), followed by Nature Reviews Microbiology (seven papers) and Antimicrobial Agents and Chemotherapy (seven papers). In addition, Science had the highest total citations (3,678) with six publications. But, the highest average citation count per publication (n = 844) belonged to Nature Reviews Drug Discovery. The Spearman rank test indicated that the number of published papers (p = 0.255), total citations (p = 0.300), and average citation count per publication (p = 0.439) did not correlate to the 2021 IFs (Supplementary Figure S2).

TABLE 2.

Journals of the top 100 cited publications on bacterial persisters.

Journal Number of publications Total citations Average citation count per paper 2021 IF
Journal of Bacteriology 8 2,354 294 3.476
Nature Reviews Microbiology 7 3,553 508 78.297
Antimicrobial Agents and Chemotherapy 7 1,199 171 5.938
Nature 6 2,754 459 69.504
Science 6 3,678 613 63.798
Proceedings of the National Academy of Sciences 4 1,101 275 12.779
Cell 3 955 318 66.85
Molecular Cell 3 718 239 19.328
Nature Chemical Biology 3 869 289 16.29
Plos Genetics 3 789 263 6.02
Science Translational Medicine 2 665 332 19.359
Nature Communications 2 310 155 17.694
Annual Review of Microbiology 2 1,386 693 16.232
Mbio 2 458 229 7.786
Current Opinion in Microbiology 2 429 214 7.584
Applied and Environmental Microbiology 2 618 309 5.005
Molecular Microbiology 2 585 292 3.979
Plos One 2 430 215 3.752
Journal of Medical Microbiology 2 428 214 3.196
Nature Reviews Drug Discovery 1 844 844 112.288
Lancet infectious Diseases 1 233 233 71.421
Clinical Microbiology Reviews 1 148 148 50.129
Cell Host and Microbe 1 261 261 31.316
Nature Immunology 1 481 481 31.25
Nature Microbiology 1 303 303 30.964
Trends in Microbiology 1 151 151 18.23
Biotechnology Advances 1 423 423 17.681
FEMS Microbiology Reviews 1 163 163 15.177
Trends in Biochemical Sciences 1 211 211 14.264
Journal of Internal Medicine 1 484 484 13.068
Molecular Systems Biology 1 158 158 13.068
Plos Medicine 1 294 294 11.613
Plos Biology 1 475 475 9.593
Cell Chemical Biology 1 148 148 9.039
Journal of Medicinal Chemistry 1 265 265 8.039
Plos Pathogens 1 167 167 7.464
Clinical Pharmacology & therapeutics 1 381 381 6.903
Frontiers in Cellular and infection Microbiology 1 508 508 6.073
Expert Review of Anti-infective therapy 1 149 149 5.854
Environmental Microbiology 1 153 153 5.476
Virulence 1 182 182 5.428
Toxins 1 157 157 5.075
Scientific Reports 1 154 154 4.996
Current Topics in Microbiology and Immunology 1 517 517 4.737
BMC Microbiology 1 421 421 4.465
Genetics 1 384 384 4.402
International Journal of Medical Microbiology 1 783 783 3.658
Future Microbiology 1 187 187 3.553
Biochemical and Biophysical Research Communications 1 168 168 3.322
Biochemistry-Moscow 1 311 311 2.824
FEMS Microbiology Letters 1 695 695 2.82
Open in a new tab

Countries, institutions, and authors

A total of 14 countries contributed to the top 100 cited publications on bacterial persisters (Table 3). The United States was the most productive country in this field with 64 publications. England ranked second with eight publications, followed by Israel (seven publications), Belgium (five publications), and Switzerland (three publications). Furthermore, the United States was also the most influential country on bacterial persisters with the highest total citations (23,129). New Zealand had the highest average citation count per publication (508).

TABLE 3.

Countries of the top 100 cited publications on bacterial persisters.

Country a Number of publications Total citations Average citation count
United States 64 23,130 361
England 8 2,676 334
Israel 7 2,239 320
Belgium 5 1,194 239
Switzerland 3 681 227
Sweden 2 924 462
Denmark 2 678 339
Canada 2 576 288
France 2 314 157
New Zealand 1 508 508
Netherlands 1 207 207
China 1 202 202
India 1 160 160
Spain 1 149 149
Open in a new tab
a

The country distributions were extracted based on the country of first author.

Fifty five institutions participated in the top 100 cited publications, therein, 15 institutions have published two or more papers (Table 4). Most of these institutions were from the United States (13 institutions, 87%), and only one institution each from Israel and England. Northeastern University was the most prolific institution with 20 publications and total citations of 9,451, followed by The Hebrew University of Jerusalem (7 publications, 2,239 citations) and Boston University (5 publications, 1,885 citations). Rockefeller University ranked fourth in terms of the number of publications (3), but had the highest average citation count per publication (805).

TABLE 4.

Institutions with more than two papers in the top 100 cited publications on bacterial persisters.

Institution a Country Number of publications Total citations Average citation count
Northeastern University United States 20 9,451 472
The Hebrew University of Jerusalem Israel 7 2,239 320
Boston University United States 5 1,885 377
The Rockefeller University United States 3 2,415 805
Harvard University United States 3 464 155
University of North Dakota United States 2 430 215
University of Illinois United States 2 428 214
Tulane University United States 2 301 150
Texas A&M University United States 2 452 226
Princeton University United States 2 375 188
Pennsylvania State University United States 2 532 266
Newcastle University England 2 772 386
Johns Hopkins University United States 2 317 158
Brown University United States 2 583 292
Broad Institute of MIT & Harvard United States 2 348 174
Open in a new tab
a

The institution distributions were extracted based on the institution of first author.

A total of 437 authors contributed to the top 100 cited publications on bacterial persisters. Among them, 13 first authors and 13 last authors published at least two papers. As shown in Table 5, Kim Lewis from Northeastern University was the most contributing author who published five first-author papers and 13 last-author papers. In terms of the first authors, Nathalie Q. Balaban from Rockefeller University and Iris Keren from Northeastern University both published three papers. It was worth noting that four first authors (Iris Keren; Brian P. Conlon; Tobias Dörr; Amy L. Spoering) were from Northeastern University, and the last author of their publications was Kim Lewis. For the last authors, James J. Collins from Boston University ranked second with six publications, followed by Kenn Gerdes from University of Copenhagen (five publications).

TABLE 5.

Authors with more than two first-author or last-author publications in the top 100 cited publications on bacterial persisters.

First author Last author
Author Institution Number of papers Author Institution Number of papers
Kim Lewis Northeastern University 5 Kim Lewis Northeastern University 13
Nathalie Q. Balaban The Rockefeller University 3 James J. Collins Boston University 6
Iris Keren Northeastern University 3 Kenn Gerdes University of Copenhagen 5
Brian P. Conlon Northeastern University 2 Nathalie Q. Balaban The Hebrew University of Jerusalem 4
Jose Luis Del Pozo Clinical University of Navarra 2 Thomas K. Wood Texas A&M University 4
Tobias Dörr Northeastern University 2 John D. McKinney The Hebrew University of Jerusalem 3
Sarah Schmidt Grant Broad Institude of MIT & Harvard 2 Michael R. Barer University of London 2
Alexander Harms University of Copenhagen 2 Mark P. Brynildsen Princeton University 2
Shaleen B. Korch University of North Dakota 2 Thomas M. Hill University of North Dakota 2
Etienne Maisonneuve Newcastle University 2 Deborah T. Hung Broad Institude MIT & Harvard 2
Amy L. Spoering Northeastern University 2 Stanislas Leibler The Rockefeller University 2
Laurence Van Melderena University of Libre Bruxelles 2 Jan Michiels Katholieke University Leuven 2
Xiaoxue Wang Brown University 2 Marin Vulić Northeastern University 2
Open in a new tab

Keywords and subject categories

Figure 3 showed the co-occurrence network of author keywords and keywords plus. The meaningless words were manually excluded and the same meaning words were merged. The most frequently occurring keywords in the top 100 cited publications were “Escherichia coli” (57 times), “persisters” (44 times), “Pseudomonas aeruginosa” (29 times), “multidrug tolerance” (25 times), “biofilms” (25 times), “mechanism” (20 times), “stress response” (17 times). Accordingly, the keywords in the network were divided into six clusters. Four clusters were separated by the research objects, including Mycobacterium tuberculosis (red), E. coli (blue), P. aeruginosa (green), and Staphylococcus aureus (yellow). From the results of co-occurrence, current researches on bacterial persisters mainly focused on 1) the role of persisters in biofilm (yellow); and 2) the mechanism of persisters formation (purple and light blue).

FIGURE 3.

FIGURE 3

Open in a new tab

Co-occurrence network of keywords identified from top 100 cited publications on bacterial persisters. The red cluster was about the in vitro and in vivo studies on Mycobacterium tuberculosis. Researches on E. coli (blue cluster), P. aeruginosa (green cluster), and S. aureus (yellow cluster) have also been extensively studied. The yellow cluster was also focused on the role of persisters in biofilm. The purple cluster and the light blue cluster were about the mechanism of persisters formation.

A total of 12 subject categories were extracted from the WoSCC. Among them, “Microbiology” was the most frequent category with 40 publications, followed by “Multidisciplinary Sciences” with 21 publications and “Biochemistry and Molecular Biology” with 18 publications. Consistent with the number of publications, the subject categories of “Microbiology” (13,088 citations) and “Multidisciplinary Sciences” (8,427 citations) had the highest total frequency of citation. Furthermore, the subject category of “Biotechnology and Applied Microbiology” had the highest average citation count per publication (n = 471).

Discussion

In this study, a bibliometric study was performed to identify and analyze the top 100 cited publications on bacterial persisters. Commonly, the citation frequency of publication reflected the importance of the paper, which also indicated its scientific recognition by researchers in the relevant field, and how it generated discussion or triggered new research direction (Fardi et al., 2017; Tarazona et al., 2018). Moreover, the highly cited publication was suggested as a milestone study in the related field (Van Noorden et al., 2014). Hence, the top 100 cited publications included in this study could be identified as “classics” in the field of bacterial persisters, and the bibliometric analysis of “classics” emphasized researchers, research outputs, and future research trends (Godin, 2006).

In this study, the top 100 cited papers on bacterial persisters were published between 1997 and 2019. Among them, 2009 to 2014 was the productive period of highly cited publication on bacterial persisters (a total of 52 publications), and 2013 was found to have the most publications. The increase of publications between 2009 and 2014 indicated that more attention was paid to the field of bacterial persisters by researchers, or there were several important scientific breakthroughs during this period. The growth rate of citations increased significantly after 2009 also reflecting increasing research interest in bacterial persisters.

The citation frequency of each publication was between 147 and 1815 (WoSCC); 153 and 1883 (Scopus); 207 and 2,986 (Google Scholar). The number of citations per publication showed significant differences between databases. The research on bacterial persisters started more than 80 years ago when Hobby and Bigger found that penicillin could not fully kill culture (Hobby et al., 1942; Bigger, 1944). Therefore, the WoSCC was selected as the benchmark as it included citation metrics from 1900 to the present. The Scopus currently included citations starting in 1960, and this is a deficiency in analyzing the most cited publications (Jafarzadeh et al., 2015). Google Scholar showed higher citation frequencies as it included books, conference proceedings, dissertations, technical reports, and preprints, in addition to scientific papers (Jafarzadeh et al., 2015; Ahmad et al., 2019).

Generally speaking, earlier publications had more time to be cited and likely achieved more citations (Picknett and Davis, 1999; Jiang et al., 2019). However, our analysis discovered that the total citation counts were not related statistically to the age of publication, which was similar to the results of other bibliometric analysis (Ahmad et al., 2019; Jiang et al., 2019). The reason might be that earlier publications are possibly no longer cited as they were absorbed by new knowledge, and publications without persistent importance are more likely to be forgotten with increasing time (Garfield, 1987; Paladugu et al., 2002). Another explanation was that researchers showed more interest in the latest developments which might give in-depth research results or trigger new research directions. This viewpoint was verified by the decreasing trend in mean citation per year with age increasing.

All the top-cited papers on bacterial persisters were published in English, that’s probably because English is the most widely used language in knowledge dissemination, and several databases had a preference for English language (Seglen, 1997b; Bondi, 2017; Zhang et al., 2021). Moreover, as institutions in United States and England made significant contributions to the field of bacterial persisters, researchers from these institutions might prefer to cite papers published in English. Among the top 100 cited publications, the number of origin articles (64) was more than review articles (35). Meanwhile, the review articles had a higher average citation count per paper (n = 377) than origin articles (n = 317). Review articles generally have higher citations than other types (Seglen, 1997a). The results also reflected that review articles were important for researchers to convey their points of view, even though new findings in origin articles have gained significant attention. We found that 62 publications were included in “Microbiology” and “Multidisciplinary Sciences” subject categories, while “Biochemistry and Molecular Biology” was the focus of 18 publications. These indicated that researches on bacterial persisters involved the cross of multi-disciplinary and researchers have been working to explore the molecular mechanisms of persisters formation.

According to our bibliometric analysis, 51 different journals published the top 100 cited publications on bacterial persister. Some of the top 100 cited papers were published in journals focusing on molecular biology or pharmacy, like Molecular Cell, Nature Chemical Biology, and Nature Reviews Drug Discovery. This was also related to the opinion that multi-disciplinary researches have increasingly concerned with the problem of bacterial persisters. In terms of IFs, 51 papers were published in journals with 2021 IFs more than 10, and 77 papers in journals had 2021 IFs more than 5. However, the Journal of Bacteriology, which published the highest number of papers in the top 100 cited list, had a relatively low IF (3.476). In addition, more than half of the top papers (51) were published in journals specializing in microbiology. These facts suggested that most researchers in the field of bacterial persisters were more favored to choose reputational and authoritative journals in their research field, not only focusing on IFs. Several other factors also influenced authors to choose journals, including the difficulty of manuscript acceptance, publication charges, time of peer review and so on (Jiang et al., 2019; Shamsi et al., 2021). On the other hand, the publication cycle time and circulation time of journals also affected the citations of papers. Usually, publications in journals with a short publication cycle time and long circulation time likely gained more citation times (Jiang et al., 2019). Furthermore, journal accessibility had an impact on the citation of publications (Eysenbach, 2006).

More than half of the top 100 cited publications (64 publications) were published in the United States, while England ranked second with eight publications. In several other bibliometric studies of similar fields, the highest number of papers was also published in the United States (Arshad et al., 2020; Liu et al., 2020; Zhu et al., 2020). This reflected the great influence of the United States in the field of pathogenic bacteria. This was probably because the United States with high GDP allots more research funding to scientific investigation and some of the world’s top research institutions are located in the United States (Peng et al., 2021; Zhang et al., 2021). Besides, authors in the United States were easier to publish their studies in American journals, and they tend to cite local publications (Paladugu et al., 2002; Peng et al., 2021). Furthermore, there were 13 institutions from the United States in the list of institutions with more than two publications, while the rest two institutions were in Israel and England respectively. Among these institutions, the studies on bacterial persisters were mainly from universities, and only one research institution called Broad Institute of MIT & Harvard. Significantly, Peking University in China had one paper in the list of top 100 cited publications, and this represented the progress in the influence of our national scientific research. Previous studies have proved that China led the scientific production in several bacterial fields, however, the quality of publications from China should be further improved (Zhu et al., 2020; Quincho-Lopez and Pacheco-Mendoza, 2021).

Kim Lewis from Northeastern University was the most prolific author with the most number of publications both as first author and last author. His studies on bacterial persisters are mainly focusing on the physiological characteristics of persisters (Shah et al., 2006) and factors affecting the formation of persisters, like oxidative stress (Wu et al., 2012), ATP dependent (Conlon et al., 2016; Shan et al., 2017), antibiotics (Doerr et al., 2010), toxin/antitoxin (Correia et al., 2006; Doerr et al., 2010). Besides, Kim Lewis is also devoted to identifying novel targets or compounds to kill persisters and eradicate persistent infections (Conlon et al., 2013; Lewis, 2013). In addition, Kim Lewis cooperated with some productive authors, like Nathalie Q. Balaban from Rockefeller University, Tobias Dörr from Northeastern University, and Marin Vulić from Northeastern University.

Keywords are highly refined research content and they provide research topics and hotspots in the field. It was worth noting that keywords are not required in every publication and several papers did not display author keywords (Harms et al., 2018; Kim et al., 2018; Balaban et al., 2019). Therefore, the keywords plus from the WoSCC database were utilized to form a relatively complete network. The keywords “Escherichia coli”, “Pseudomonas aeruginosa”, “Mycobacterium tuberculosis” and “Staphylococcus aureus” occurred more than 10 times, and this indicated that researches on bacterial persisters were mainly based on studies of these strains. In addition, the high-frequency keywords belong to the mechanism of persisters formation (including “stress response,” “toxin-antitoxin systems,” “messenger-RNA,” “murein synthesis,” “HipA,” “(p)ppGpp”) and the characteristic of persisters (including “multidrug tolerance,” “biofilms,” “antibiotic resistance,” “phenotypic heterogeneity”). These keywords were regarded as the current research hotspots and future directions, which were of considerable interest to researchers around the world.

The links between different keywords were also presented in the keywords co-occurrence visualization. Regarding the mechanism studies, 27 keywords were linked to the keyword “mechanism.” In terms of total link strength, the link strengths between “mechanism” and “phenotypic heterogeneity,” “stress response,” “metabolism,” “messenger RNA,” “oxidative stress” were ranked in sequence. Phenotypic heterogeneity is generated by epigenetic regulation and it leads to the formation of nonreplicating persisters under fluctuating selective perssures (Dhar and McKinney, 2007; Helaine et al., 2014). This can be distinguished from the mechanism of bacterial resistance which is acquired by mutations or horizontal gene transfer of resistance genes (Balaban et al., 2019). The keywords “stress response,” “messenger RNA” and “oxidative stress” were also linked to “phenotypic heterogeneity.” This was probably because the phenotypic growth arrest of persisters was generated by activating stress responses. Several stress response pathways were linked to the formation of persisters, including oxidative stress, (p)ppGpp stringent response, messenger RNA involved in Toxin-antitoxin system, SOS response (Doerr et al., 2009; Vega et al., 2012; Wu et al., 2012; Maisonneuve and Gerdes, 2014; Sala et al., 2014). Keywords “inhibition,” “peptidoglycan,” “murein synthesis,” and “DNA synthesis” in the light blue cluster were related to the toxin protein HipA, which is a member of the bacterial toxin-antitoxin modules. The hipA gene regulated the establishment of a persistent state through inhibition of murein synthesis, DNA synthesis, and peptidoglycan synthesis, as well as induction of (p)ppGpp synthesis (Korch et al., 2003) (Moyed and Bertrand, 1983). The development of compounds that interfered with these pathways was an alternative strategy to kill persisters (Tkachenko et al., 2021; Kaushik et al., 2022). Furthermore, Bacterial persisters are in a state of reduced metabolism. It has been reported that carbon metabolism, nucleotide metabolism, and fatty acids metabolism were involved in the formation of bacterial persisters (McKinney et al., 2000; Hansen et al., 2008; Kotte et al., 2014). Therefore, the combination of metabolic stimuli and antibiotics (like aminoglycosides) enhanced the ability to kill persisters (Allison et al., 2011).

The role of persisters in biofilms has been extensively studied, and the keyword “biofilms” was linked to 51 (63.8%) keywords. There were strong link strengths between “biofilms” and “persisters,” this was because biofilms induce the formation of persisters, and persisters in biofilm are largely responsible for the resistance of biofilms (Lewis, 2001). Several keywords, like “toxin antitoxin system,” “stress response,” “messenger RNA,” and “oxidative stress” were linked to both “mechanism” and “biofilms.” During pathogenesis, bacteria often form a mature three-dimensional biofilm architecture through secreting extracellular matrix and cell division. In biofilms, bacteria are under the condition of nutrient limitation and therefore activing the (p)ppGpp involved stress response and triggering toxin-mediated antibiotic tolerance (Nguyen et al., 2011; Maisonneuve and Gerdes, 2014). These render the bacterial population less susceptible to antibiotics in the microenvironment conditions of biofilms, and also facilitated the formation of persisters in biofilms (Wang and Wood, 2011; Romling and Balsalobre, 2012). In addition, there were several antimicrobial agents linked to the keyword “biofilms,” such as “antibiotic,” “tobramycin,” and “beta-lactam.” Although persisters and biofilms were tolerant to antimicrobial (Keren et al., 2004), the use of antibiotics in combination with compounds to eradicate both persisters and biofilms has become a possible therapeutic strategy. For example, manifests enhanced the activity of tobramycin against P. aeruginosa infections (Meylan et al., 2017). However, there were relatively few keywords concerning strategies against persisters. The main reason was that the specific regulatory network for persister formation was not particularly clear. This led to few efficient targets for the development of novel inhibitors. In-depth mechanism studies were urgently needed and it continued to be the future hot spot. Furthermore, the identification of compounds with novel targets against persisters was helpful to solve the problem of chronic infection in the clinic.

To our knowledge, this study was the first bibliometric analysis to identify the top 100 cited publications on bacterial persisters. There were some limitations as with other bibliometric analyses. First, the truncated search terms “persister$”, “persisten*” and “toleran*” were utilized to define the research topics in the WoSCC database, some related publications were not included in the analysis as the diversity of the keywords. Second, although the literature search had no language restriction, it appears that only English-language studies were included in the bibliometric analysis. There were language biases in this study. Third, the top 100 cited publications were sorted by the number of total citations, while the citation frequency of publications is affected by several factors, like authors, institutions, language, and journals’ IF. In addition, earlier publications tend to achieve more citations, and some recent papers with high academic value were out of consideration as they don’t have enough time to accumulate citations. Regardless of publication year, the mean citation per year was an alternative indicator to identify the most influential publication. Moreover, self-citations have a substantial influence on the citation-based metric and this might introduce potential bias in bibliometrics. Finally, this study was a cross-sectional study and the identified top 100 cited publications could change in the future.

Conclusion

We performed a bibliometric study of the top 100 cited publications related to bacterial persisters. These papers were published from 1997 to 2019 in 51 journals and the citation frequency of these publications presented a rising trend. The United States contributed greatly to the highly cited publications on bacterial persisters. Professor Kim Lewis from Northeastern University was the most productive author. Based on the results of keywords co-occurrence, it was found that the researches on bacterial persisters mainly focused on exploring the mechanism of persister formation or re-growth. This study provided research trends on bacterial persisters, and these might help researchers and clinical workers to better understand the classic studies and new findings in this field.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Author contributions

YJ contributed to designe and performe the experiment, as well as write the original draft. HL, PZ, and PX contributed to screen the publications and visualizing analysis. LS and YB contributed to analyze the data and formal analysis. PY and YZ contributed to review and edit the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2022.1001861/full#supplementary-material

Click here for additional data file. (2.9MB, docx)

References

  1. Ahmad P., Dummer P. M. H., Noorani T. Y., Asif J. A. (2019). The top 50 most‐cited articles published in the International Endodontic Journal. Int. Endod. J. 52, 803–818. 10.1111/iej.13083 [DOI] [PubMed] [Google Scholar]
  2. Allison K. R., Brynildsen M. P., Collins J. J. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220. 10.1038/nature10069 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson G., Dodson K., Hooton T., Hultgren S. (2004). Intracellular bacterial communities of uropathogenic Escherichia coli in urinary tract pathogenesis. Trends Microbiol. 12, 424–430. 10.1016/j.tim.2004.07.005 [DOI] [PubMed] [Google Scholar]
  4. Arshad A. I., Ahmad P., Karobari M. I., Asif J. A., Alam M. K., Mahmood Z., et al. (2020). Antibiotics: A bibliometric analysis of top 100 classics. Antibiotics 9, 219. 10.3390/antibiotics9050219 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Balaban N. Q., Helaine S., Lewis K., Ackermann M., Aldridge B., Andersson D. I., et al. (2019). Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441–448. 10.1038/s41579-019-0196-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Balaban N. Q., Merrin J., Chait R., Kowalik L., Leibler S. (2004). Bacterial persistence as a phenotypic switch. Science 305, 1622–1625. 10.1126/science.1099390 [DOI] [PubMed] [Google Scholar]
  7. Bigger J. (1944). Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497–500. 10.1016/S0140-6736(00)74210-3 [DOI] [Google Scholar]
  8. Bondi M. (2017). Knowledge dissemination across media in English: Continuity and change in discourse strategies, ideologies, and epistemologies, PRIN. Impact 2017, 64–66. 10.21820/23987073.2017.9.64 [DOI] [Google Scholar]
  9. Chen L., Wen Y. (2011). The role of bacterial biofilm in persistent infections and control strategies. Int. J. Oral Sci. 3, 66–73. 10.4248/IJOS11022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cohen N. R., Lobritz M. A., Collins J. J. (2013). Microbial persistence and the road to Drug resistance. Cell Host Microbe 13, 632–642. 10.1016/j.chom.2013.05.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Conlon B. P., Nakayasu E. S., Fleck L. E., Lafleur M. D., Isabella V. M., Coleman K., et al. (2013). Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365–370. 10.1038/nature12790 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Conlon B. P., Rowe S. E., Gandt A. B., Nuxoll A. S., Donegan N. P., Zalis E. A., et al. (2016). Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat. Microbiol. 1, 16051. 10.1038/NMICROBIOL.2016.51 [DOI] [PubMed] [Google Scholar]
  13. Correia F. F., D’Onofrio A., Rejtar T., Li L., Karger B. L., Makarova K., et al. (2006). Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli . J. Bacteriol. 188, 8360–8367. 10.1128/JB.01237-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. den Bergh B., Fauvart M., Michiels J. (2017). Formation, physiology, ecology, evolution and clinical importance of bacterial persisters. FEMS Microbiol. Rev. 41, 219–251. 10.1093/femsre/fux001 [DOI] [PubMed] [Google Scholar]
  15. Dhar N., McKinney J. D. (2007). Microbial phenotypic heterogeneity and antibiotic tolerance. Curr. Opin. Microbiol. 10, 30–38. 10.1016/j.mib.2006.12.007 [DOI] [PubMed] [Google Scholar]
  16. Doerr T., Lewis K., Vulic M. (2009). SOS response induces persistence to fluoroquinolones in Escherichia coli . PLoS Genet. 5, e1000760. 10.1371/journal.pgen.1000760 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Doerr T., Vulic M., Lewis K. (2010). Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli . PLoS Biol. 8, e1000317. 10.1371/journal.pbio.1000317 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Domingue G. J., Woody H. B. (1997). Bacterial persistence and expression of disease. Clin. Microbiol. Rev. 10, 320–344. 10.1128/CMR.10.2.320-344.1997 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Eysenbach G. (2006). Citation advantage of open access articles. PLoS Biol. 4, e157. 10.1371/journal.pbio.0040157 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fardi A., Kodonas K., Lillis T., Veis A. (2017). Top-cited articles in implant dentistry. Int. J. Oral Maxillofac. Implants 32, 555–564. 10.11607/jomi.5331 [DOI] [PubMed] [Google Scholar]
  21. Fisher R. A., Gollan B., Helaine S. (2017). Persistent bacterial infections and persister cells. Nat. Rev. Microbiol. 15, 453–464. 10.1038/nrmicro.2017.42 [DOI] [PubMed] [Google Scholar]
  22. Garfield E. (1987). 100 citation classics from the journal of the American medical association. JAMA J. Am. Med. Assoc. 257, 52–59. 10.1001/jama.1987.03390010056028 [DOI] [PubMed] [Google Scholar]
  23. Godin B. (2006). On the origins of bibliometrics. Scientometrics 68, 109–133. 10.1007/s11192-006-0086-0 [DOI] [Google Scholar]
  24. Hansen S., Lewis K., Vulic M. (2008). Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli . Antimicrob. Agents Chemother. 52, 2718–2726. 10.1128/AAC.00144-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harms A., Brodersen D. E., Mitarai N., Gerdes K. (2018). Toxins, targets, and triggers: An overview of toxin-antitoxin biology. Mol. Cell 70, 768–784. 10.1016/j.molcel.2018.01.003 [DOI] [PubMed] [Google Scholar]
  26. Helaine S., Cheverton A. M., Watson K. G., Faure L. M., Matthews S. A., Holden D. W. (2014). Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343, 204–208. 10.1126/science.1244705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hobby G. L., Meyer K., Chaffee E. (1942). Observations on the mechanism of action of penicillin. Exp. Biol. Med. (Maywood). 50, 281–285. 10.3181/00379727-50-13773 [DOI] [Google Scholar]
  28. Jafarzadeh H., Sarraf Shirazi A., Andersson L. (2015). The most-cited articles in dental, oral, and maxillofacial traumatology during 64 years. Dent. Traumatol. 31, 350–360. 10.1111/edt.12195 [DOI] [PubMed] [Google Scholar]
  29. Jiang Y., Hu R., Zhu G. (2019). Top 100 cited articles on infection in orthopaedics: A bibliometric analysis. Medicine 98, e14067. 10.1097/MD.0000000000014067 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kaushik V., Sharma S., Tiwari M., Tiwari V. (2022). Antipersister strategies against stress induced bacterial persistence. Microb. Pathog. 164, 105423. 10.1016/j.micpath.2022.105423 [DOI] [PubMed] [Google Scholar]
  31. Keren I., Kaldalu N., Spoering A., Wang Y. P., Lewis K. (2004). Persister cells and tolerance to antimicrobials. FEMS Microbiol. Lett. 230, 13–18. 10.1016/S0378-1097(03)00856-5 [DOI] [PubMed] [Google Scholar]
  32. Kim W., Zhu W., Hendricks G. L., Van Tyne D., Steele A. D., Keohane C. E., et al. (2018). A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556, 103–107. 10.1038/nature26157 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Korch S. B., Henderson T. A., Hill T. M. (2003). Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol. Microbiol. 50, 1199–1213. 10.1046/j.1365-2958.2003.03779.x [DOI] [PubMed] [Google Scholar]
  34. Kotte O., Volkmer B., Radzikowski J. L., Heinemann M. (2014). Phenotypic bistability in Escherichia coli’s central carbon metabolism. Mol. Syst. Biol. 10, 736. 10.15252/msb.20135022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Levin-Reisman I., Ronin I., Gefen O., Braniss I., Shoresh N., Balaban N. Q. (2017). Antibiotic tolerance facilitates the evolution of resistance. Science 355, 826–830. 10.1126/science.aaj2191 [DOI] [PubMed] [Google Scholar]
  36. Lewis K. (2013). Platforms for antibiotic discovery. Nat. Rev. DRUG Discov. 12, 371–387. 10.1038/nrd3975 [DOI] [PubMed] [Google Scholar]
  37. Lewis K. (2001). Riddle of biofilm resistance. Antimicrob. Agents Chemother. 45, 999–1007. 10.1128/AAC.45.4.999-1007.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Liu X., Wu X., Tang J., Zhang L., Jia X. (2020). Trends and development in the antibiotic-resistance of acinetobacter baumannii: A scientometric research study (1991–2019). Infect. Drug Resist. 13, 3195–3208. 10.2147/IDR.S264391 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mack D., Becker P., Chatterjee I., Dobinsky S., Knobloch J. K. M., Peters G., et al. (2004). Mechanisms of biofilm formation in Staphylococcus epidermidis and Staphylococcus aureus: functional molecules, regulatory circuits, and adaptive responses. Int. J. Med. Microbiol. 294, 203–212. 10.1016/j.ijmm.2004.06.015 [DOI] [PubMed] [Google Scholar]
  40. Maisonneuve E., Gerdes K. (2014). Molecular mechanisms underlying bacterial persisters. Cell 157, 539–548. 10.1016/j.cell.2014.02.050 [DOI] [PubMed] [Google Scholar]
  41. Martinecz A., Abel zur Wiesch P. (2018). Estimating treatment prolongation for persistent infections. Pathog. Dis. 76, fty065. 10.1093/femspd/fty065 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. McKinney J. D., zu Bentrup K. H., Munoz-Elias E. J., Miczak A., Chen B., Chan W. T., et al. (2000). Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735–738. 10.1038/35021074 [DOI] [PubMed] [Google Scholar]
  43. Meylan S., Porter C. B. M., Yang J. H., Belenky P., Gutierrez A., Lobritz M. A., et al. (2017). Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control. Cell Chem. Biol. 24, 195–206. 10.1016/j.chembiol.2016.12.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Monack D. M., Mueller A., Falkow S. (2004). Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat. Rev. Microbiol. 2, 747–765. 10.1038/nrmicro955 [DOI] [PubMed] [Google Scholar]
  45. Moyed H. S., Bertrand K. P. (1983). hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155, 768–775. 10.1128/jb.155.2.768-775.1983 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Nadri H., Rahimi B., Timpka T., Sedghi S. (2017). The top 100 articles in the medical informatics: a bibliometric analysis. J. Med. Syst. 41, 150. 10.1007/s10916-017-0794-4 [DOI] [PubMed] [Google Scholar]
  47. Nguyen D., Joshi-Datar A., Lepine F., Bauerle E., Olakanmi O., Beer K., et al. (2011). Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982–986. 10.1126/science.1211037 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Paladugu R., Schein M., Gardezi S., Wise L. (2002). One hundred citation classics in general surgical journals. World J. Surg. 26, 1099–1105. 10.1007/s00268-002-6376-7 [DOI] [PubMed] [Google Scholar]
  49. Pang Z., Raudonis R., Glick B. R., Lin T.-J., Cheng Z. (2019). Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol. Adv. 37 (1), 177–192. 10.1016/j.biotechadv.2018.11.013 [DOI] [PubMed] [Google Scholar]
  50. Peng M.-S., Chen C.-C., Wang J., Zheng Y.-L., Guo J.-B., Song G., et al. (2021). The top 100 most-cited papers in long non-coding RNAs: a bibliometric study. Cancer Biol. Ther. 22, 40–54. 10.1080/15384047.2020.1844116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Picknett T., Davis K. (1999). The 100 most-cited articles from JMB. J. Mol. Biol. 293, 171–176. 10.1006/jmbi.1999.3148 [DOI] [PubMed] [Google Scholar]
  52. Quincho-Lopez A., Pacheco-Mendoza J. (2021). Research trends and collaboration patterns on polymyxin resistance: A bibliometric analysis (2010–2019). Front. Pharmacol. 12, 702937–703012. 10.3389/fphar.2021.702937 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Romling U., Balsalobre C. (2012). Biofilm infections, their resilience to therapy and innovative treatment strategies. J. Intern. Med. 272, 541–561. 10.1111/joim.12004 [DOI] [PubMed] [Google Scholar]
  54. Sala A., Bordes P., Genevaux P. (2014). Multiple toxin-antitoxin systems in Mycobacterium tuberculosis . Toxins (Basel) 6, 1002–1020. 10.3390/toxins6031002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Seglen P. O. (1997a). Citations and journal impact factors: questionable indicators of research quality. Allergy 52, 1050–1056. 10.1111/j.1398-9995.1997.tb00175.x [DOI] [PubMed] [Google Scholar]
  56. Seglen P. O. (1997b). Why the impact factor of journals should not be used for evaluating research. BMJ 314, 498–502. 10.1136/bmj.314.7079.497 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Shah D., Zhang Z., Khodursky A., Kaldalu N., Kurg K., Lewis K. (2006). Persisters: a distinct physiological state of E-coli. BMC Microbiol. 6, 53. 10.1186/1471-2180-6-53 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Shamsi A., Lund B. D., SeyyedHosseini S., BasirianJahromi R. (2021). Journal selection behavior among early-career academicians in Iran: how they choose the most appropriate journal for their publications. Glob. Knowl. Mem. Commun. [Epub ahead of print]. 10.1108/GKMC-09-2021-0146 [DOI] [Google Scholar]
  59. Shan Y., Gandt A. B., Rowe S. E., Deisinger J. P., Conlon B. P., Lewis K. (2017). ATP-dependent persister formation in Escherichia coli . MBio 8, e02267. 10.1128/mBio.02267-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Singh P. K., Schaefer A. L., Parsek M. R., Moninger T. O., Welsh M. J., Greenberg E. P. (2000). Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407, 762–764. 10.1038/35037627 [DOI] [PubMed] [Google Scholar]
  61. Spoering A. L., Lewis K. (2001). Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J. Bacteriol. 183, 6746–6751. 10.1128/JB.183.23.6746-6751.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tarazona B., Lucas-Dominguez R., Paredes-Gallardo V., Alonso-Arroyo A., Vidal-Infer A. (2018). The 100 most-cited articles in orthodontics: A bibliometric study. Angle Orthod. 88, 785–796. 10.2319/012418-65.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Tkachenko A. G., Kashevarova N. M., Sidorov R. Y., Nesterova L. Y., Akhova A. V., Tsyganov I. V., et al. (2021). A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting (p)ppGpp synthetases. Cell Chem. Biol. 28, 1420–1432. 10.1016/j.chembiol.2021.01.018 [DOI] [PubMed] [Google Scholar]
  64. Tsai Y.-L., Lee C.-C., Chen S.-C., Yen Z.-S. (2006). Top-cited articles in emergency medicine. Am. J. Emerg. Med. 24, 647–654. 10.1016/j.ajem.2006.01.001 [DOI] [PubMed] [Google Scholar]
  65. van Eck N. J., Waltman L. (2017). Citation-based clustering of publications using CitNetExplorer and VOSviewer. Scientometrics 111, 1053–1070. 10.1007/s11192-017-2300-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. van Eck N. J., Waltman L. (2010). Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics 84, 523–538. 10.1007/s11192-009-0146-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Van Noorden R., Maher B., Nuzzo R. (2014). The top 100 papers. Nature 514, 550–553. 10.1038/514550a [DOI] [PubMed] [Google Scholar]
  68. Vega N. M., Allison K. R., Khalil A. S., Collins J. J. (2012). Signaling-mediated bacterial persister formation. Nat. Chem. Biol. 8, 431–433. 10.1038/NCHEMBIO.915 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Wang C.-Y., Li B.-H., Ma L.-L., Zhao M.-J., Deng T., Jin Y.-H., et al. (2019). The top-100 highly cited original articles on Drug therapy for ventilator-associated pneumonia. Front. Pharmacol. 10, 108–117. 10.3389/fphar.2019.00108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Wang X., Wood T. K. (2011). Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. Appl. Environ. Microbiol. 77, 5577–5583. 10.1128/AEM.05068-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Wu Y., Vulic M., Keren I., Lewis K. (2012). Role of oxidative stress in persister tolerance. Antimicrob. Agents Chemother. 56, 4922–4926. 10.1128/AAC.00921-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Zhang S., Fan H., Zhang Y. (2021). The 100 top-cited studies on dyslexia research: A bibliometric analysis. Front. Psychiatry 12, 714627. 10.3389/fpsyt.2021.714627 [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Zhang Y., Huang J., Du L. (2017). The top-cited systematic reviews/meta-analyses in tuberculosis research: A PRISMA-compliant systematic literature review and bibliometric analysis. Med. Baltim. 96, e4822. 10.1097/MD.0000000000004822 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Zhang Y. (2014). Persisters, persistent infections and the Yin–Yang model. Emerg. Microbes Infect. 3, e3–10. 10.1038/emi.2014.3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Zhang Y., Quan L., Xiao B., Du L. (2019). The 100 top-cited studies on vaccine: a bibliometric analysis. Hum. Vaccin. Immunother. 15, 3024–3031. 10.1080/21645515.2019.1614398 [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Zhu Y., Li J. J., Reng J., Wang S., Zhang R., Wang B. (2020). Global trends of Pseudomonas aeruginosa biofilm research in the past two decades: A bibliometric study. Microbiologyopen 9, 1102–1112. 10.1002/mbo3.1021 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Click here for additional data file. (2.9MB, docx)

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA

RESOURCES