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. 2024 Jul 24;17(7):e14537. doi: 10.1111/1751-7915.14537

Metal‐regulated antibiotic resistance and its implications for antibiotic therapy

Zeling Xu 1,✉, Xiaoshan Lin 2
PMCID: PMC11267348  PMID: 39045888

Abstract

Antibiotic resistance, one of the major medical threats worldwide, can be selected and induced by metals through multiple mechanisms such as co‐resistance, cross‐resistance, and co‐regulation. Compared with co‐resistance and cross‐resistance which are attributed to the physically or functionally linked metal and antibiotic resistance genes, co‐regulation of antibiotic resistance genes by metal‐responsive regulators and pathways is much more complex and elusive. Here, we discussed the main mechanisms by which antibiotic resistance is regulated in response to metals and showed recent attempts to combat antibiotic resistance by interfering with metal‐based signalling pathways. Further efforts to depict the intricate metal‐based regulatory network of antibiotic resistance will provide tremendous opportunities for the discovery of novel anti‐resistance targets, and blocking or rewiring the metal‐based signalling pathways is emerging as a promising stratagem to reverse bacterial resistance to antibiotics and rejuvenate the efficacy of conventional antibiotics.

Metal ions play an important role in modulating the expression of antibiotic resistance determinants. This article discussed the main mechanisms by which antibiotic resistance is regulated in response to metals and showed recent attempts to combat antibiotic resistance by targeting metal‐based signalling pathways.

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ANTIBIOTIC RESISTANCE: A GROWING THREAT TO THE GLOBAL PUBLIC HEALTH

The discovery and application of antibiotics have saved a lot of lives and economic losses over the past century. However, with the long‐time imprudent use of antibiotics, bacteria have developed serious resistance to almost all the currently prescribed antibiotics through various mechanisms such as restricted uptake and active extrusion of antibiotics, inactivation of antibiotics, protection of cellular antibiotic targets, and alternative pathways to bypass the antibiotic toxicity (Darby et al., 2023). Antibiotic resistance has become one of the top medical challenges threatening human health. The emergence of antibiotic‐resistant pathogens has led to the loss of hundreds and thousands of lives every year and it is predicted that the number of annual deaths will increase to 10 million by 2050 without effective solutions to slow the ever‐increasing trend of antibiotic resistance (Jim, 2016; Murray et al., 2022).

Overuse and misuse of antibiotics are the key factors leading to the rapid emergence and spread of antibiotic resistance genes. Apart from numerous attempts to discover and develop novel antibiotics, an important strategy to mitigate antibiotic resistance is the restriction of antibiotic usage, which has been adopted by many countries in the last decade (Casewell et al., 2003; Ma et al., 2021). However, it is noted that antibiotic resistance is still prevalent in natural and clinical settings and remains a growing threat to the global public health (Rahman et al., 2023; Sundqvist et al., 2010), suggesting that there are more than just antibiotics, and also the presence of additional agents that can induce antibiotic resistance.

METALS ARE UBIQUITOUS AGENTS INDUCING ANTIBIOTIC RESISTANCE

Metals are ubiquitous in nature, and they are generally beneficial to bacteria as they are indispensable micronutrients that are required to maintain cellular functions and support normal growth (Palmer & Skaar, 2016). However, metals are also cytotoxic and display antimicrobial activities in certain forms and concentrations. For example, excessive metals frequently damage the structures of nucleic acids, proteins as well as cell membranes to disrupt basic cellular functions and impede cell growth (Lemire et al., 2013). Thus, metal ions have been used as antimicrobial agents since ancient times and new approaches involving metal nanoparticles or metal complexes are being developed to combat antibiotic resistance (Frei et al., 2023; Tomić & Vuković, 2022; Wang et al., 2021). Humans and other vertebrate hosts have evolved to utilize metal‐based nutritional immunity to defend against invading pathogens by modulating metal concentrations at the host–pathogen interface during bacterial infection (Hood & Skaar, 2012; Murdoch & Skaar, 2022). Like antibiotic resistance, bacteria have developed sophisticated adaptive responses to the alterations of metal concentrations, and thus cellular metal homeostasis in bacteria is tightly maintained through various actions such as the activation of metal import, efflux, and storage (Chandrangsu et al., 2017).

Owing to their antimicrobial activity, antibiotics and metals have been used in combination to treat infectious diseases. However, the combined use often exhibits selective effects on the emergence of bacterial resistance to multiple antibiotics. For example, the co‐occurrence of copper and tetracycline has been shown to considerably elevate the resistance of antibiotic‐susceptible bacterial strains to multiple antibiotics such as chloramphenicol and polymyxin (Li et al., 2021). Increased resistance to antibiotic along with increasing metal concentrations has been widely observed in diverse environments, including the clinical, aquatic, agricultural, and industrial settings (Nguyen et al., 2019). Thus, metals have been increasingly recognized as critical factors driving the selection, evolution, and spread of antibiotic resistance (Chen et al., 2015; Pal et al., 2017; Poole, 2017; Tongyi et al., 2020; Zhang et al., 2019).

MECHANISMS OF METAL‐INDUCED ANTIBIOTIC RESISTANCE

Metals select antibiotic resistance in bacteria through multiple mechanisms: co‐resistance, cross‐resistance, and co‐regulation (Figure 1) (Murray et al., 2024; Zhao et al., 2024). In recent decades, a growing number of evidence has shown that antibiotic resistance selected in response to metal excess is associated with the physically or functionally linked metal and antibiotic resistance genes (Vats et al., 2022). Co‐resistance occurs when genes responsible for metal and antibiotic resistance are physically located on a single genetic element, particularly a mobile genetic element (MGE) such as a plasmid. Bacterial strains with simultaneous resistance to metals and antibiotics are selected during metal excess, and co‐occurrence of the metal and antibiotic resistance genes on MGEs provides a great opportunity for the spread of antibiotic resistance across different bacterial species and environments. In contrast to different genes, cross‐resistance happens when a single gene encodes a multifunctional detoxification apparatus, such as an efflux pump, that can confer resistance to both metals and antibiotics simultaneously. In addition to the physically and functionally linked resistance genes, bacteria exhibit inducible and adaptive antibiotic resistance in response to metals. Co‐regulation indicates that metals act as common signals to induce the expression of both metal and antibiotic resistance genes.

FIGURE 1.

FIGURE 1

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Mechanisms of metal‐selected antibiotic resistance. Co‐resistance: Physically linked MRG and ARG in a same genetic element. Cross‐resistance: Functionally linked genes for metal and antibiotic resistance. Co‐regulation: Regulation of MRG and ARG by a common metal‐responsive regulator or signalling pathway. ARG, antibiotic resistance gene; MRG, metal resistance gene.

REGULATION OF ANTIBIOTIC RESISTANCE BY METALS

Bacterial stress adaptation depends on their elaborate signal sensing and transduction systems. Distinct from co‐resistance and cross‐resistance, co‐regulation of antibiotic resistance in response to metals is relatively elusive and less understood, as it usually involves abundant regulatory proteins or small RNAs (sRNAs) and intricate signalling pathways or cellular processes. Metals regulate antibiotic resistance mainly through the modulation of the abundance of antibiotic influx or efflux systems, modifications of membrane lipopolysaccharide (LPS), generation of intracellular reactive oxygen species (ROS), biofilm formation, and so forth (Figure 2 and Table 1). For example, the one‐component system (OCS) MarR is a copper (Cu2+) sensor that derepresses the marRAB operon in an oxidized form in the presence of Cu2+ and subsequently induces bacterial resistance to multiple antibiotics by activating the expression of the efflux pump AcrAB‐TolC through the global regulator MarA (Hao et al., 2014; Keeney et al., 2008). Cu2+ can also be perceived by two‐component systems (TCSs) such as CopS/CopR which induces imipenem resistance by repressing the expression of the porin protein OprD (Caille et al., 2007). Zinc (Zn2+) can be sensed by the TCS CzcS/CzcR which induces imipenem resistance by also repressing the expression of OprD (Perron et al., 2004; Wang et al., 2017). Similarly, ferric iron (Fe3+) can be perceived by the TCS PmrA/PmrB, which activates the expression of PbgP and Ugd for the modification of LPS layers and consequently induces polymyxin resistance (Wösten et al., 2000).

FIGURE 2.

FIGURE 2

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Regulation of antibiotic resistance by metals. Metals regulate antibiotic resistance through the modulation of the abundance of antibiotic influx porins and other uptake or efflux systems, LPS modifications, intracellular ROS generation, biofilm formation, etc.

TABLE 1.

Major mechanisms of antibiotic resistance (AR) that are regulated by metals.

AR mechanism Regulator Metal signal Microorganism References
Antibiotic efflux OCS (MarR) Cu2+ Escherichia coli Hao et al. (2014)
TCS (CzcS/CzcR) Zn2+ Pseudomonas aeruginosa Chen et al. (2023)
Antibiotic uptake TCS (CopS/CopR) Cu2+ P. aeruginosa Caille et al. (2007)
TCS (CzcS/CzcR) Zn2+ P. aeruginosa Perron et al. (2004)
sRNA (RyhB) Fe3+ E. coli Chareyre et al. (2019)
LPS modification TCS (PmrA/PmrB) Fe3+ Salmonella Wösten et al. (2000)
TCS (ColS/ColR) Zn2+ P. aeruginosa Nowicki et al. (2015)
ROS prevention ? Fe3+ Streptomyces coelicolor, Mycobacterium smegmatis Choi et al. (2022)
Biofilm formation ? Zn2+, ZnO Streptococcus pneumoniae, Pseudomonas putida Brown et al. (2017) and Ouyang et al. (2020)
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Bacterial responses to external stresses are complex. Alterations in metal concentrations often result in a reprogrammed transcriptome in bacteria, with the expression of different antibiotic resistance determinants being influenced by a single metal and its responsive regulatory system. Although CzcS/CzcR is known to increase imipenem resistance during Zn2+ excess, it was recently found that CzcS/CzcR also represses multidrug efflux pumps, in particular MexAB‐OprM, which reduces Pseudomonas aeruginosa resistance to aminoglycoside and fluoroquinolone antibiotics during Zn2+ excess (Chen et al., 2023). In addition, the TCS ColS/ColR can be activated by Zn2+ to induce LPS modification and polymyxin resistance in P. aeruginosa (Nowicki et al., 2015). Co‐regulation of different antibiotic resistance determinants is common under the treatment of the same or different metals. Even in some cases, a metal can divergently regulate the resistance and susceptibility of bacterial cells to the same antibiotic. As another example, Fe3+, which activates PmrA/PmrB‐mediated LPS modification for increased polymyxin resistance in Escherichia coli (Herrera et al., 2010), could also increase the resistance of E. coli cells to gentamicin by lowering intracellular gentamicin concentration through undetermined mechanisms (Huang et al., 2022). Interestingly, Fe3+ was also found to promote proton motive force (pmf)‐based gentamicin uptake and attenuate E. coli resistance to gentamicin by negatively regulating the expression of the sRNA RyhB (Chareyre et al., 2019).

It is generally accepted that exposure to bactericidal antibiotics results in accelerated aerobic respiration and generation of ROS, causing oxidative damage and cell death (Dwyer et al., 2014; Kohanski et al., 2007). Therefore, reduction or clearance of ROS can increase bacterial resistance to bactericidal antibiotics (Lobritz et al., 2015). It was found in actinobacterial species Streptomyces coelicolor and Mycobacterium smegmatis that Fe3+ can promote bacterial resistance to bactericidal antibiotics by altering respiration to possibly avoid ROS generation (Choi et al., 2022). Biofilm, a community of bacterial cells embedded in a self‐produced matrix of extracellular polymeric substances (EPS), promotes the elevation of antibiotic resistance by blocking the access of antibiotics to bacterial cells residing in the matrix (Flemming & Wingender, 2010). Biofilm formation is an adaptive strategy for bacterial survival under stress conditions and metals are important signals that regulate the formation or disruption of biofilms. Many metals or metal nanoparticles such as Zn2+ and ZnO nanoparticles have been reported to induce biofilm formation in different bacterial species at certain concentrations (Brown et al., 2017; Ouyang et al., 2020).

TARGETING METAL‐BASED SIGNALLING PATHWAYS TO TACKLE ANTIBIOTIC RESISTANCE

Metals play an important role in regulating bacterial antibiotic resistance. Due to the sluggish pace of new antibiotic discovery and development, extensive efforts have been made in recent years to look for adjuvants to potentiate the efficacy of existing antibiotics by modulating metal concentrations or rewiring the metal‐based signalling pathways. For example, by establishing a screening platform that mimics the host milieu, Zhong et al. found three catechol‐type flavonoids that were capable of converting Fe3+ to Fe2+, which blocked the PmrA/PmrB‐mediated colistin resistance and functioned effectively to synergize with colistin for the treatment of bacterial infections (Zhong et al., 2023). In another study, Gadar et al. identified kaempferol as a potentiator of the antimicrobial activity of colistin by screening a library of phytochemicals, which was shown to overcome both intrinsic and acquired colistin resistance through dysregulation of Fe homeostasis (Gadar et al., 2023). The potentiating effects of flavonoids and kaempferol were confirmed in infection models such as mice or Galleria mellonella, providing proof‐of‐concept demonstrations that targeting metal‐based signalling pathways or disrupting metal homeostasis is a promising strategy to combat antibiotic resistance.

CONCLUSIONS AND FUTURE PERSPECTIVES

With the policy of banning the use of antibiotics as feed supplements in livestock production in many countries, metals have received increasing attention as alternative feed supplements and have been widely used in animal feed due to their antimicrobial and growth‐promoting effects (Seiler & Berendonk, 2012). In addition, pollution caused by various anthropogenic activities, including agricultural, industrial and mining activities, has resulted in elevated metal concentrations in the soils and waters (Briffa et al., 2020). Metals do not degrade and can easily accumulate in the environment. The widespread metals inevitably provide persistent selective pressure for the evolution and proliferation of antibiotic resistance in bacteria, exacerbating concerns about the transmission of antibiotic resistance genes among humans, animals, and the environment under the One Health framework. Metal‐induced co‐selection of antibiotic resistance has become one of the greatest challenges in fighting against antibiotic resistance, leading to an ever‐increasing global public health threat that has not been significantly reduced even with the strict control of antibiotic usage (Rahman et al., 2023).

Metals are naturally present in the ecosystem, and most metals that induce antibiotic resistance are known to be essential micronutrients for all kinds of life including human hosts (Zoroddu et al., 2019). Restriction of metals access to bacteria seems impossible, and thus metals represent a widespread and long‐standing selective pressure that induces antibiotic resistance. Identification of antibiotic resistance determinants that are co‐selected by metals is crucial to unveil targets for anti‐resistance applications. However, direct targeting towards antibiotic resistance determinants to help eliminate antibiotic‐resistant pathogens appears to be difficult as well. For example, a series of efflux pump inhibitors (EPIs) have been discovered and designed to efficiently reverse antibiotic‐resistant strains to susceptible strains in vitro by physically blocking the antibiotic efflux channels, but none of them has been approved for clinical use due to the side effects of cytotoxicity (Zimmermann et al., 2019).

Apart from metal‐selected co‐resistance and cross‐resistance, metals also serve as signals to regulate the expression of antibiotic resistance genes in addition to metal resistance genes. Co‐regulation provides alternative targets for anti‐resistance exploitations. However, co‐regulation of antibiotic resistance comprises complicated signalling networks involving various regulatory systems or cellular processes. Additionally, cross‐talk among different metal signalling pathways is widely present in bacteria (Li et al., 2024; Xu et al., 2019), making it more difficult to elucidate the connections between antibiotic resistance and a specific metal signal. Moreover, bacterial responses to a particular metal differ among bacterial species or strains. Therefore, a deep and comprehensive understanding of the complicated regulatory network that mediates antibiotic resistance in response to different metal signals in different pathogens is desired, which will provide precise targets and tremendous opportunities for the development of antibiotic adjuvants to turn down the expression of antibiotic resistance genes, helping to rejuvenate the efficacy of the conventional antibiotic regimens to deal with certain infections.

AUTHOR CONTRIBUTIONS

Zeling Xu: Conceptualization; writing – original draft; writing – review and editing; funding acquisition. Xiaoshan Lin: Writing – review and editing.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest with the contents of this article.

ACKNOWLEDGEMENTS

This work was supported by the National Natural Science Foundation of China (Nos. 32370188 and 32100020) and the Guangdong Basic and Applied Basic Research Foundation (Nos. 2023A1515012775 and 2022A1515010194).

Xu, Z. & Lin, X. (2024) Metal‐regulated antibiotic resistance and its implications for antibiotic therapy. Microbial Biotechnology, 17, e14537. Available from: 10.1111/1751-7915.14537

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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