Streptococcus suis: Epidemiology and resistance evolution of an emerging zoonotic bacteria

Abstract

The health of humans and the growth of the agriculture industry are seriously threatened by the emerging zoonotic pathogen Streptococcus suis (S. suis). In the last decades, evolutionary studies have significantly enhanced our understanding of S. suis. Currently, S. suis is widespread across numerous countries, in which it displays diverse serotypes and complex population structures. The widespread use of antibiotics across the globe has resulted in significant multi-drug resistance among clinical isolates of S. suis, creating a serious challenge in treating infections and presenting a considerable risk to public health and safety. This article briefly describes the transmission routes and infection symptoms of S. suis between different species, particularly in pigs and humans. The epidemiological situation and differences of S. suis in humans and pigs are further analyzed from three aspects of serotype, MLST, and WGS. Finally, the latest research progress on drug resistance mechanism of S. suis was reviewed. A deep understanding of the epidemiological situation and antimicrobial resistance characteristics of S. suis is crucial for crucial for mitigating the emergence of superbugs and for innovating new molecules or combinations of antimicrobials.

1. Introduction

Streptococcus suis (S. suis, SS) is an aerobic or facultative anaerobic Gram-positive, coccoid or ovoid, and exists in pairs and/or short chains bacterium [1]. As shown in Fig. 1, a scanning electron microscope image illustrates the morphology of S. suis. This pathogen causes disease in humans such as meningitis, endocarditis, arthritis and sepsis, seriously leading to death [2]. S. suis infects the host by penetrating the skin-mucous membrane barrier and entering the bloodstream, leading to the invasion of different tissues and organs, resulting in the development of diseases [3]. Furthermore, it has the ability to traverse the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier, gaining access to the central nervous system (CNS) and causing meningitis [2]. Over 100 virulence-associated genes have been identified as being linked to the pathogenesis of S. suis virulent strains [[4], [5], [6]]. Therefore, S. suis has drawn significant attention in the fields of public health and medicine [7].

Fig. 1.

Three distinct perspectives of S. suis observed under varying magnification levels. A. Macroscopic observation of colony morphology in agar culture. B. Gram staining observed under an inverted microscope. C. Scanning electron microscope image.

Based on the antigenicity of the capsular polysaccharide (CPS), 29 authentic S. suis serotypes (1–19, 21, 23–25, 27–31, and 1/2), serotype Chz and 27 novel cps loci (NCLs) have been classified [[8], [9], [10], [11]]. S. suis, as a zoonotic disease, is widespread across the world, and it has become one of the most frequently reported infectious diseases affecting pigs in recent years. This pathogen poses a significant threat to the swine breeding industry, causing serious economic losses on a global scale [12,13]. S. suis has disseminated across more than 30 countries and regions, with a particularly high prevalence in Southeast Asian nations [14], and it has led to fatal infection outbreaks across Asia [6]. So, S. suis is regarded as a significant emerging zoonotic agent.

Considering that vaccines offer only limited protection against specific serotypes of S. suis, the swine industry has heavily relied on antibiotics to control S. suis infections. This reliance has contributed to a global rise of antimicrobial-resistant (AMR) strains [15]. Taking into account the “One Health” framework, the well-being of humans, animals, and the environment is interlinked. Bacterial drug resistance interacts closely with the environment. The spread of antibiotic resistance can be transmitted in humans, animals and the environment through different pathways. The environment promotes the spread of drug resistance through horizontal transfer of drug resistance genes, stress screening, etc. Additionally, the existence of antibiotic resistance genes (ARGs) and the proliferation of extremely drug-resistant bacteria represent a significant risk to public health [16]. Alarmingly, S. suis strains are exhibiting an upward trend in resistance rates in various nations, including America, Asia, and Europe [17,18]. As a result, understanding the resistance mechanisms of S. suis is critical for developing effective strategies to treat infections. This review begins by briefly outlining the transmission routes and clinical symptoms associated with S. suis infections. Then, the epidemiological situation of S. suis in recent years is described from two aspects of serotype and MLST. Finally, it highlights the latest research advancements in understanding the mechanisms underlying S. suis antibiotic resistance.

2. Transmission routes

Pigs are the primary host of S. suis, and piglets are the most susceptible. However, S. suis has been isolated from a diverse range of host species, including birds, rabbits, dogs, cats, cows, horses, oxen, fawns, and wild boars [1]. This broad spectrum of affected animals underscores the global prevalence of S. suis and highlights the complexity introduced by its ability to infect such a wide variety of species.

Healthy pigs naturally harbor multiple serotypes of S. suis in their upper respiratory tract [19]. The transmission of S. suis occurs via two primary modes: vertical transmission during the sow's delivery of piglets and horizontal transmission through nose-to-nose contact between pigs [20]. Increasing evidence indicates that airborne transmission is an important route of short-distance transmission of S. suis. Outbreaks of S. suis in pig nurseries usually occur with the introduction of subclinically infected pigs into the herd [21]. And these introduced pigs carried potentially pathogenic strains into herds and pig nurseries, leading to the increased rate of disease outbreaks [22]. Such findings shown that the spread of S. suis can also be transmitted by aerosols.

So far, there is no direct evidence to suggest that S. suis is transmitted from person to person [23]. Wound exposure to pigs and pork remains one of the most important ways for contracting S. suis. Human infection predominantly occurs through close contact with contaminated animals, carcasses or meat [24]. For instance, in countries such as the United Kingdom, Spain, Germany, the Netherlands, Canada, the United States, Japan, China, most reported cases of S. suis infection among humans have been linked to occupational exposure involving pig handing. This includes professions such as pig farmers, bleeders, abattoir workers, carcass cutting and processing workers, butchers, and cooks [25]. In addition, infections have been frequently reported after ingestion of contaminated pig products, indicating that S. suis can also be transmitted through the oral route [26]. In Southeast Asian countries, such as Thailand, Vietnam, and Indonesia, a notable number of human cases have been traced to the consuming meals containing raw pork meat, blood, and other related products [27]. Furthermore, inadequate food safety controls of raw pork products at pig slaughterhouses and fresh markets serve as critical sources of human infection with S. suis [28]. A limited number of cases have been reported in North America, particularly in the United States and Canada, Here, S. suis infections have predominantly been associated with individuals who failed to utilize protective sanitary measures such as gloves or masks while handling or slaughtering dead or diseased pigs [29,30]. The transmission routes and infection symptoms of S. suis were shown in Fig. 2.

Fig. 2.

Transmission routes and infection symptoms of S. suis. S. suis is transmitted through aerosols that enable it to colonizes the upper respiratory tract of pigs [31]. Infections caused by S. suis present with symptoms such as meningitis, arthritis, and occasionally pneumonia [32]. S. suis was transmitted vertically to piglets [20]. Humans primarily become infected through the ingestion of contaminated pork products or via pathogens entering through skin wounds [33]. After breaking through the human mucosal barrier, S. suis invades different tissues, organs and brain of the human body through blood circulation and other methods, mainly leading to the occurrence of sepsis, endocarditis, arthritis, meningitis and other diseases [34,35]. Beyond pigs and humans, S. suis has also been identified as a pathogen in other animals, such as zebra finches, mice and cats, causing symptoms such as sepsis, bacterial meningitis and endocarditis [[36], [37], [38]].

3. Epidemiology

Serotyping is commonly employed to analyze the epidemiology of the outbreak, monitor the prevalence of specific S. suis serotypes, and guide the development of vaccines [39]. According to variations in the antigenicity of CPS, S. suis are classified into 29 serotypes, Chz and 27 novel cps loci (NCLs) [[8], [9], [10], [11]]. The distribution of S. suis serotypes varies by time and location [11]. Generally, serotype 2 was considered as the most virulent serotype, and in infections associated with S. suis, serotypes 3, 7, and 9 are also frequently associated with infections in many countries [40].

In Europe, serotypes 9 and 2 are the most common serotypes in pigs, followed by serotypes 7, 8, 3, 1, and 4 [41]. In Italy, Belgium, France, Germany, the Netherlands, Spain, and the United Kingdom, serotype 9 is the most prevalent, followed by serotypes 2 and 7 [42,43]. Serotype 1 have been identified in France, the Netherlands, the United Kingdom, Spain, and Germany. Serotypes 3 and 1/2 have been isolated from Germany and France. Serotypes 4, 8 and 10 are exclusively reported in Germany, the United Kingdom and the Netherlands, while France is the only country where serotypes 5, 16, 18 and 23 were found [43]. In Asia, serotype 2 is predominant among S. suis strains isolated from sick pigs, though serotypes 1/2,3, 8, 9, 21, 29 and 31 were also reported [44]. In China and Vietnam, the most prevalent serotype among S. suis isolated from infected pigs was serotype 2 [45,46], followed by serotype 4 [11]. In Japan, serotype 2 is also the leading serotype, followed by serotype 5 [47,48]. In Thailand, serotype 2 or 1/2 are the most prevalent, followed by serotypes 29, 8, 9 and 21 [49]. In the Philippines, serotype 31 is reported as the most prevalent [50]. In South Korea, serotypes 3 and 2 were most widespread among diseased pigs [40]. In North America, the leading serotypes differ slightly between countries. In the United States, the separation rates of serotypes 1, 1/2, and 7 were the highest, with serotype 2 following closely [51,52]. In Canada, serotypes 1/2 and 2 were dominant, followed by serotypes 7, 3, 5, 4, 9, 1 and 14 [53]. The similar distribution of serotypes between U.S. and Canada may be related to mobile transmission of animals [26]. In Mexican pig farms, serotype 9 is the most prevalent train among sick animals showed that, with serotypes 7 and 8 following closely behind [54]. In South America, Brazil chiefly reports serotype is 2, with serotypes 1/2, 14, 7, and 9 following closely behind [55,56]. Serotype testing of clinical cases in pig herds in Australia and New Zealand showed that serotype 2 is the most dominant, followed by serotype 1 and 3 [57,58]. And serotype 2 is a serotype that has appeared in Africa [59]. Fig. 3 shows the major serotypes of S. suis affecting pigs across different continents.

Fig. 3.

Global distribution of the main prevalent serotypes of S. suis infecting pigs. The serotypes of S. suis exhibit notable variation, and not all are pathogenic [66]. The main serotype affecting pig herds globally is type 2, with other serotypes distributed differently across continents.

As shown in Table 1, the main serotypes of S. suis infected humans were serotype 2, followed by serotypes 7, 9, 31, 24, 5, and 25. Men constitute the predominant group affected by these infections. In China, a woman was reported to have been infected with S. suis serotype 7, presenting with severe inflammation in both lungs [8]. In Thailand, Serotypes 9 [60] and 31 [61] were identified in infected men, while a case involving serotype 24 was recorded in a woman [62]. In Sweden, a man was infected with S. suis serotype 5 [63]. And in the United States, both serotypes 5 [64] and 25 [65] have been found to infect humans.

Table 1.

The report enumerated various ST categories of human clinical S. suis infections spanning from 2013 to 2024.

Country	Gender	Clinical diagnosis	Serotype	ST	References
Asia
China	male	purulent meningitis and sepsis	2	7	[76]
		purulent meningitis and sepsis	2	7	[76]
		purulent meningitis and bilateral knee arthritis	2	–	[77]
		acute multiple brain infarctions	2	–	[34]
		meningitis and sepsis	–	–	[78]
		spinal canal infection	–	–	[79]
		suppurative meningitis	2	–	[80]
		endogenous endophthalmitis and meningitis	–	–	[81]
	–	septicemia and hepatic dysfunction	2	25	[82]
	female	inflammation of both lungs.	7	373	[8]
		meningoencephalitis	–	–	[83]
		purulent meningitis	2	–	[84]
		stiffness and meningeal irritation	–	–	[85]
		meningitis	2	–	[86]
South Korea	male	subdural empyema	2	–	[87]
India	female	chronic osteomyelitis	2	–	[88]
Japan	male	meningitis with ventriculitis	–	–	[89]
		meningitis and pyogenic ventriculitis	2	1	[90]
		toxic shock-like syndrome	2	–	[91]
		toxic shock-like syndrome	2	–	[92]
		bacterial meningitis	2	28	[93]
Vietnam	male	endophthalmitis, meningitis, and septicemia	2	–	[94]
Thailand	male	diagnosed with septic shock	9	16	[60]
		sepsis	31	221	[61]
		sepsis meningitis septicarthritis	2	1656	[95]
		meningitis, septicaemia and spondylodiscitis	–	–	[96]
	female	septic meningitis	24	–	[62]
		acute suppurative thyroiditis	–	–	[97]
	ND	ND	24	221, 234	[98]
Indonesia	male	acute bacterial meningitis	2	–	[99]
		meningitis	–	–	[100]
		meningitis	–	–	[101]
	female	pneumonia	–	–	[102]
Philippines	male	bacterial meningitis	–	–	[103]
Malaysia	male	meningitis	–	–	[104]
Europe
Portugal	male	Acute bacterial meningitis	–	–	[105]
Spain	male	disseminated cancer	–	3	[106]
		meningitis	2	3	[107]
		meningitis, septic arthritis	–	–	[108]
Sweden	male	septic arthritis	5	–	[63]
Hungary	male	purulent meningitis	2	–	[109]
		meningeal excitatory signs	2	–	[109]
		acute ischemic lesions	2	–	[109]
		purulent meningitis	–	–	[110]
Lithuania	male	bacterial meningitis	–	–	[111]
Greece	male	meningitis	–	–	[112]
France	male	meningitis and bacteremia	2	1	[113]
Italy	–	meningitis	2	1	[114]
Czech	–	septicemia	2	1	[24]
The United Kingdom	–	meningitis	2	1708	[24]
North America
The United States	male	toxic shock like syndrome	5	–	[64]
		meningitis	25	–	[65]
Canada	male	hearing loss and neurologic status deteriorated	2	25	[115]
Africa
The Republic of Togo	male	meningitis	2	1	[116]
Madagascar	female	meningitis	2	834	[117]
Argentina	male	purulent meningitis	–	–	[118]
South America
Chile	female	acute bacterial meningitis	2	–	[119]
	male	acute bacterial meningitis	2	–	[119]
Brazil	male	meningitis	–	–	[120]
		meningitis	2	–	[121]

Multilocus sequence typing (MLST) is a reliable system for characterizing isolates by sequence analysis of housekeeping genes [67]. MLST data are variable and informative, allowing seamless transfer and comparison across different laboratories. Therefore, MLST is regarded as the benchmark for studying bacterial pathogen populations. The MLST technique has been extensively employed to assess the diversity, worldwide distribution, and epidemiology of S. suis populations [68]. Establishing an MLST protocol for S. suis involves seven housekeeping genes: cpn60, dpr, recA, aroA, thrA, gki, and mutS [69]. Additionally, S. suis species exhibit multiple sequence types (STs). When MLST is used in conjunction with serotyping, it enables the collection of significantly more comprehensive data about the genetic diversity of S. suis strains with distinct serotypes.

A variety of ST types with regional differences have been identified. MLST investigations on S. suis strains obtained from sick pigs have revealed that the majority were serotype 2. Currently, ST1, ST25, and ST28 have been identified as the most common ST types in pigs, according to the global MLST study of S. suis [51,70]. In North America, the distribution of strains showed that 44 % were ST25, 51 % were ST28, and 5 % were ST1. In the United States and Canada, the ST of S. suis is mainly ST28, followed by ST1 and ST25 [51]. In Europe, ST1 and ST16 (associated with S. suis serotype 9) are the most frequently encountered. Among the S. suis strains isolated from pigs in Belgium, France, Germany, Hungary, the Netherlands, Spain, and the United Kingdom, ST16 and ST1 dominated, followed by ST29 and ST1552 [43]. In the Czech, the predominant ST is ST29, followed by ST28, ST1, ST54, ST87, ST2074 and ST17 [71]. In Asia, MLST analysis of serotype 2 strains revealed that ST1 and ST7 are most common, while a smaller proportion of strains were identified as ST28 [26]. In China, The main STs are ST1 and ST7 [72], and Fig. 4 illustrates the geographic distribution of the ST types of S. suis infecting humans across various provinces and regions in China. In Japan, ST1 and ST28 were the most frequently observed STs [73]. In South America, the ST found in Argentina was ST1 [74]. And in Australia, ST27 and ST25 were dominant [57].

Fig. 4.

Geographical distribution of ST types of S. suis infecting humans in different regions and provinces of China. Based on the MLST database and previous studies, the key sequence types of *S. suis* responsible for human infections in China are ST7 and ST1 [75]. In addition, other sequence types (ST242, ST377, ST658, ST665, ST945, ST1005, ST1131, ST1132, ST1711, ST1718, ST1853, ST1228, and ST2145) were gradually discovered in different regions(https://pubmlst.org/ssuis).

As shown in Table 1, the report enumerated various ST categories of human clinical S. suis infections spanning from 2013 to 2024. Globally, ST1 strains were considered as the main cause of human cases of S. suis serotype 2, but other ST types have also been reported in human infections. In China，S. suis strains ST7, ST25, and ST373 have been found in human infections. In Japan, ST1 and ST28 have been documented. In Thailand, ST16, ST221, ST1656, and ST234 have been reported. In Spain, ST3 were reported. And in France, Italy, Czech and Lome have reported only ST1 in human infections. Additionally, human cases of ST1708, ST25 and ST834 have been reported in the United Kingdom, Canada and Madagascar, respectively.

Bacterial whole genome sequencing (WGS) has emerged as a widely-used technique in research, clinical diagnostic, and public health laboratories [122]. Data derived from WGS can be analyzed using an array of bioinformatics tools, which provide information about the quality of sequenced genomes and identify species, strains, and genotypes of the infecting organisms. Furthermore, these tools facilitate predictions regarding drug susceptibility or resistance and support epidemiological investigations [123]. To better comprehend the mechanisms underlying the emergence of cross-species transmission and virulence in humans, Dong et al. showed the formation of a novel human-associated clade (HAC) diversified from swine S. suis isolates. Their study found that HAC comprises three sub-lineages, including several healthy-pig isolates which display high virulence in experimental infections. This suggests that healthy-pig carriers may serve as a potential reservoir for human infection [124]. Murray et al. found that several pathogenic lineages of S. suis are distinguished by the presence of three genomic islands that likely play roles in metabolism and cell adhesion. And they also observed an an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology [125]. These studies provide invaluable insights into the genetic diversity, and antimicrobial susceptibility of S. suis isolates, facilitating the identification of emerging clones that pose significant concerns for public health.

4. Mechanisms of Antimicrobial Resistance (AMR)

In the pig industry, antimicrobials have historically been utilized to either prevent or manage S. suis infections in pigs, ensuring that consumers receive safer pork products [126]. Penicillin has been the primary treatment option, either used alone or in combination with aminoglycosides, macrolides, lincosamides, fluoroquinolones, and tetracyclines [127]. However, the persistent and widespread use of antimicrobials in both pigs and humans has resulted in the emergence of antimicrobial resistance, turning it into a worldwide issue [128]. The widespread and inappropriate application of antibiotics in both human and veterinary practices represents the primary selective force driving the rapid development and distribution of bacterial resistance globally [129]. Notably, S. suis has been recognized for functioning as a reservoir of antimicrobial resistance, which promotes the dissemination of antibiotic resistance genes to other streptococcal pathogens. Consequently, it is crucial to assess the antimicrobial susceptibility of S. suis while investigating the mechanisms underlying its resistance to drugs. As shown in Table 2, this is the situation regarding the antibiotic resistance rates of S. suis-related resistant genes and antibiotics. And Fig. 5 shows the mechanisms related to drug resistance of S. suis.

Table 2.

AMR genes and antibiotic resistance rate of S. suis.

Antibiotic category	AMR genes	Resistance rate	References
Tetracyclines	tet(O/W/32/O)、tet(O/32/O)、tetW、tet40、tetO、tetM、tetL、tetB、tetK、tetS	96.6 % of 29 SS2 to tetracycline, 31.82 % of 44 SS to doxycycline, 100 % of 19 SS to doxycycline.	[15,130,131]
Lincosamides	lnu(A)、lnu(B)、lnu(C)、lnu(D)、lnu(E)、lnu(F)	96.9 % of 96 SS to clindamycin, 98.7 % of 223 SS to clindamycin.	[127,132]
Quinolones	parA、parC、gyrA、gyrB	69 % of 29 SS to ciprofloxacin, 63.35 % of 107 SS to enrofloxacin, 71.02 % of 107 SS to ofloxacin.	[15,133]
Amide alcohols	optrA、cfr	86.2 % of 29 SS to florfenicol, 89.7 % of 29 SS to chloramphenicol.	[15]
Aminoglycosides	ant1、ant(6′)-Ia、ant(6′)-Ib、ant(9′)-Ia、aac(6′)、aph(6)-Ia、aph(3′)-IIIa	59.09 % of 44 SS to streptomycin, 82.8 % of 29 SS to gentamicin, 93.18 % of 44 SS2 to kanamycin, 36.36 % of 44 SS to neomycin.	[15,130]
β-lactams	pbp2a pbp2b、pbp1a、pbp2x	13.64 % of 44 SS to penicillin, 18.9 % of 217 SS to amoxicillin, 22.72 % of 44 SS to ampicillin.	[15,130,131,134]
Macrolides	erm(B)、erm(C)、erm(TR)、mef(A)、mef(E)、cfr、mph(C)	100 % of 29 SS to erythromycin, 90.6 % of 96 SS to tilmicosin, 100 % of 19 SS to tylosin, 68.22 % of 107 SS to clarithromycin.	[15,127,131,133]
Sulfonamides	dhfr	69.5 % of 223 SS to Sulfonamide cotrimoxazole.	[132]
Pleurotus truncatula	lsa(E)、optrA、cfr、vga(F)	19.8 % of 96 SS to tiamulin, 8.3 % of 96 SS to warnemulin.	[127]
Oxazolidinones	optrA、cfr	50 % of 8 SS to linezolid.	[128]

Fig. 5.

Mechanisms related to drug resistance of S. suis. Mechanisms of resistance to antibiotics in individual S. suis, including inactivation or downregulation of antibiotic-modifying enzymes, porins, increases in efflux pumps, mutations or modifications of the antibiotic targets, and the antibiotics affected by each resistance mechanism.

5. β-lactam antibiotics

β-lactam antibiotics are a large class of antibiotics, mainly including penicillin, amoxicillin, clavulanic acid, cephalosporins, carbapenems, and monobactams [135]. β-lactam antibiotics demonstrate their bactericidal effects by forming covalent bonds with and subsequently inactivating enzymes known as penicillin-binding proteins (PBPs), consequently affecting the formation and remodeling of the bacterial peptidoglycan [136]. PBPs are found in bacterial membranes as part of enzymes that form the layer of peptidoglycan, a key component of bacterial cell wall that is important for bacterial survival [137]. Based on activities, PBPs were divided into three categories: category A (with glycosyltransferase activity as well as transpeptidase activity), category B (transpeptidases) and category C (carboxypeptidases and endopeptidases) [138]. The primary element contributing to resistance against β-lactam antibiotics is mutations in penicillin-binding proteins (PBPs). These mutations can impact enzyme catalysis, alter binding site affinity, affect stability, or result in changes to structural configuration, ultimately causing a reduction in the affinity for β-lactam [139].

Four PBPs-PBP1a, PBP2a, PBP2b and PBP2x-have been identified-in S. suis [140]. Nichari Bamphensin analyzed the four pbp genes (pbp2x, pbp2b, pbp1a, and pbp2a) of S. suis strain R61, and discovered the substitutions of multiple amino acid through prodecting the translation protein sequences of these genes [140]. The majority of amino acid replacements were observed in PBP2X and PBP2B [141]. Mutations in pbp2b and pbp2x caused Streptococci to develop moderate levels of drug resistance. And, if these genes and pbp1a gene mutate at the same time, it will cause high-level drug resistance [142]. The amount of PBP2x protein modification increased in drug-resistant strains of S. suis. Molecular dynamics simulations indicated that altering the residues Ala320, Gln553, and Thr595 in PBP2x influences the shape of the drug-binding pocket, consequently decreasing the binding affinity of drugs that activate the penicillin-binding protein PBP2x [143].

6. Aminoglycosides

Aminoglycosides are a class of antibiotics with a broad range of activity that disrupt protein synthesis by inducing errors in DNA coding, obstructing the translation of mRNA and tRNA, and hindering the recycling of ribosomes [144,145]. However, the emergence of bacterial resistance has limited their effectiveness. Bacteria employ various mechanisms to develop resistance to aminoglycosides [146], including transport alterations, ribosomal alterations, and enzymatic modification [147]. In clinical contexts, the most common mechanism of drug inactivation is the action of aminoglycoside-modifying enzymes (AMEs) [148]. And the leading cause of aminoglycoside resistance of S. suis is that multiple genes encoding AMEs alter their compounds, resulting in the inactivation of the antibiotic [135].

AMEs were categorized into three major categories: aminoglycoside acetyltransferases (AAC), aminoglycoside nucleotidyl transferases (ANT), and aminoglycoside phosphotransferases (APH) [149]. According to the position of aminoglycoside modification, AMEs were further divided into subtypes. ANT transfers AMP from ATP to the hydroxyl group at the 2′′, 3′′, 4′, 6′ or 9′ position on the aminoglycoside, including five nucleotidyl transferases: ANT(2), ANT(3), ANT(4), ANT(6) and ANT(9) [150]. APH catalyzes the ATP-dependent phosphorylation of hydroxyl groups on aminoglycoside antibiotics and includes seven phosphotransferases: APH(2), APH(3), APH(4), APH(6), APH(7) and APH(9) [151]. AAC acetylates amino groups at different positions on aminoglycosides and includes four acetyltransferases: AAC(1), AAC(2), AAC(3), and AAC(6) [152].

Part of the gene encoding ANT, ant 1 [153], ant (6′)-Ia [154], ant (6′)-Ib [153], and ant (9′)-Ia [8], have been identified in aminoglycoside-resistant S. suis isolates. The aac(6′) gene coding for ANTs has been identified in resistant strains of S. suis from Asia [8,153,154], and these isolates had high aminoglycoside MIC values [155]. The aac(6′) gene frequently combines with various genes, which code for distinct aminoglycoside-modifying enzymes, resulting in the formation of bifunctional enzymes [156]. It has been reported that there were several genes encoding only APH variants in S. suis, such as aph(3′)-IIIa and aph(6)-Ia [157,158]. To date, numerous AMEs have been identified, and they have become the primary mechanisms of aminoglycoside resistance globally [159]. However, the function of AMEs remains uncertain, but they can be spread horizontally between bacteria via plasmids, integrons, or transposons [160].

7. Tetracyclines

Tetracyclines are a class of broad-spectrum antibiotics that against Gram-positive and Gram-negative bacteria [135]. Tetracyclines attach to the 30S ribosomal subunit, preventing protein synthesis by obstructing the entry of aminoacyl-tRNA (aa-tRNA) into the A site of the ribosome [161]. Resistance to tetracyclines is typically ascribed to several factors: acquiring mobile genetic elements that harbor tetracycline-specific resistance genes, mutations occurring in the ribosome binding sites, and/or chromosomal alterations that result in enhanced expression of inherent resistance mechanisms [162]. The two mechanisms energy-dependent efflux pumps (ABC efflux pumps), ribosome protection proteins (RPP) [138,[163], [164], [165]] and enzyme inactivation (TetX) have been well described [152].

Two tetracycline resistance mechanisms of S. suis have been demonstrated: efflux pumps and RPP. Efflux pumps removes antibiotics from the cell and are encoded by genes such as tet(L), tet(B), tet(K), or tet(40) [[166], [167], [168]]. And RPP consisting of tet(O), tet(M), tet(S), tet(W), tet(O/W/32/O) or tet(O/32/O) genetic coding [169,170]. The major facilitator superfamily (MFS) includes common efflux pumps specific to tetracycline, which use proton exchange as an energy source to extrude tetracycline [171]. Transporters of MFS are divided into seven distinct groups based on the similarity in their amino acid sequences and the quantity of transmembrane segments they possess [172]. Clinically, the most common pump is the member of Group 1 or Group 2. Group 2 pumps Tet(K) and Tet(L) were found in Gram-positive bacteria [144], and they were identified together with tet (B) and tet (40) in S. suis [133,173,174]. Tet(O) and Tet(M) are the best-characterized RPPs with 75 % sequence similarity, and have been detected in tetracycline-resistant S. suis isolates [175]. TetO and TetM interact with ribosomes and catalyze the release of tetracycline from the binding site in a GTP-dependent manner [[176], [177], [178]]. Studies have shown that TetM directly removes from ribosomes and releases tetracycline through the interaction between domain IV of 16S rRNA and the tetracycline binding site [164]. TetO competes for the same ribosomal binding site as tetracycline, changing the geometry of the antibiotic binding site, displacing molecules from the ribosome and allowing protein synthesis to resume [178,179]. Other RPPs are encoded by the tet(S), tet(44), and tet(W) genes, which have been identified in S. suis isolates from Asia, North America, and Europe [153].

8. Macrolides

Macrolides are a group of antibiotics characterized by their macrolactone structures, the basic composition of which is a lactone ring of 12, 14, 15, or 16 carbon atoms, bound to a deoxysugar or amino sugar residue [147,180]. These antibiotics function by inhibiting bacterial protein synthesis, binding the 23S ribosomal RNA molecule within the 50S ribosomal subunit, and causing the cessation of bacterial protein synthesis [[181], [182], [183]]. The structure of macrolides influences the affinity and dynamics of interactions between the drug and the ribosome, while the methylation of the ribosome at the macrolide binding site can be modulated by either translation or transcription processes [184]. Several mechanisms of resistance to macrolides have been identified, such as efflux, enzymatic degradation of drugs, and mutations that alter the drug-binding pocket [185]. The increasing prevalence of resistance to macrolide antibiotics presents a significant concern [186].

Alterations in bacterial ribosomes influence ribosomal functionality and affect their susceptibility to antibiotics [187]. The Cfr protein functions as a methyltransferase, modifying the A2503 nucleotide of 23S rRNA [188]. The A2503 residue is found within overlapping antibiotic binding sites, and its methylation disrupts the positioning and attachment of the drug, thereby impairing the antibiotic's ability to bind to the ribosome [189]. The bacterial resistance to macrolide drugs are also mediated by efflux mechanism. The best-characterized examples are encoded by the mef genes (mefA and mefE), and these efflux pumps can extrude macrolide antibiotics [190]. In the Mef(E)/Mel system, macrolides are expelled from cells by Mef(E), which utilizes proton motive force as its energy source [191]. Mel displaces ribosome-bound macrolides, transferring them to Mef(E) for efflux [192]. Mef(A) and Mef(I) are part of the Mef(E) variants, which share approximately 90 % sequence identity with Mef(E) [157]. MefA is commonly found on a transposon (Tn 1207) situated within the chromosome, whereas MefE is contained in what is referred to as the “MEGA element,” a DNA segment recognized as the macrolide efflux gene assembly element [193]. Additional efflux pumps contributing to macrolide resistance in Gram-positive bacteria consist of MsrA and MsrC, both of which are part of the ABC transporter family [190].

Resistance of S. suis to macrolides has been widely reported. The primary reason for Streptococcus resistance to macrolides is the target modification mediated by the erm gene methylase, as well as an active efflux mechanism associated with the mef gene [194]. Transporters from the major facilitator superfamily (MFS), which are encoded by mef (A), mef (E), and chimeric mef (A/E) genes, play a role in countering the effects of macrolides [126,168,194]. The genes mef(A) and mef(E) have both been found in S. suis [157]. Additionally, target modifications that prevent macrolide binding also mediate macrolide resistance in S. suis. These modifications occur through enzymes that methylate macrolides at ribosomal targets and are encoded erm(B), erm(C) and erm(TR) genes [157,165]. Among these, erm(B) category is the predominant macrolide resistance factor in S. suis [195]. In flufenico-resistant Streptococcus strains from healthy pigs in China, the cfr gene has been described as involved in resistance to selected 16S member macrolides [196,197]. And macrolide phosphotransferase (MPH), encoded by the mph(C) gene, phosphorylates macrolides, thereby inactivating macrolides [157].

9. Quinolones

Quinolones consist of a fundamental bicyclic structure, which may include a fluorine atom (referred to as fluoroquinolone) along with various substituents, typically located at the C6 position [198]. Based on its fundamental composition, quinolones can be categorized into derivatives that are monocyclic, bicyclic, tricyclic, and tetracyclic [199]. Resistance to quinolone antibiotics primarily involves alterations in drug targets, the production of enzymes that modify antibiotics, and the increased efficiency of efflux pump systems [200,201]. The first mechanism involves the quinolone resistance-determining region (QRDR) of the genes gyrA, gyrB, parC, and pare [202], whose mutations can reduce sensitivity to fluoroquinolones [203,204]. Reductions in drug binding to the enzyme-DNA complex mainly happen at the S79 and D83 positions in ParC, as well as S81 and E85 in GyrA [205,206]. The second quinolone resistance gene found on plasmids is the cr variant of aac(6)-Ib (i.e., aac(6)-Ib-cr), encoding aminoglycoside acetyltransferase [207,208]. The third mechanism of resistance is based on the efflux system belonging to the ATP-binding cassette transporter family [209], which are encoded by the genes sat(A) and sat(B) [210] and has the capability to expel fluoroquinolones such as norfloxacin and ciprofloxacin.

Mutations related to quinolone resistance have been identified in S. suis, specifically within the genes gyrA, gyrB, parC, and parA [153]. Among them, quinolone resistance mutations were identified at the Ser79 and Asp83 positions within the ParC of S. suis [205], indicating that DNA gyrase can be used as the main target of quinolone drugs for the treatment of S. suis. The ABC transporter SatAB in S. suis is involved in recognizing quinolones as substrates for efflux. On the chromosome, operons contain the satA and satB genes [211], which are affected by the S. suis quorum sensing system LuxS/AI-2 regulation, thereby increasing the production of efflux pumps and contributes to a higher level of quinolone resistance [212].

10. Chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic (natural compound containing nitro group) with a novel structure. Its molecular structure consists of three parts: p-nitro, dichloroacetyl and 2-aminopropanediol [213]. The mechanisms of chloramphenicol resistance can be divided into the formation of chloramphenicol acetyltransferase (CAT) [214], mutation or modification of the target site [215], decreased membrane permeability, and the existence of multidrug efflux transporters [216]. Genes that code for CAT and particular transporters are frequently linked to mobile elements (including plasmids, transposons, and gene cassettes) [217]. The spread of cat genes and transporter genes mainly depends on the genetic elements where their respective genes are located. Chloramphenicol or fluorinated chloramphenicol derivatives (florfenicol) resistance genes can achieve cross-species spread through the transfer ability of genetic elements [66]. Currently, florfenicol is licensed for veterinary use [218]. The emergence of new resistance genes, including floR, cfr, or fexA, has been attributed to the use of florfenicol [219].

Resistance to chloramphenicol has been detected among S. suis isolates [18]. A cat-containing transposon, Tn Ss1, flanked by direct repeats of IS 6 family elements was discovered in field isolates of S. suis [220]. The transferable optrA gene in S. suis isolate SC317 exhibits high resistance to florfenicol. The optrA gene is flanked by two copies of the IS1216 element in the same direction, which is located in the prophage or ICESa2603 family integration and conjugation, component (ICE), including a series ICE [221]. The identification of the S. suis S10 strain obtained from nasal swabs of healthy pigs revealed that the cfr gene provides resistance to florfenicol in S. suis [196].

11. Lincosamide

Lincosamide is a natural antibiotic isolated from Streptomyces sp [222]. It consists of three components: amino acid, sugar (lincosamide) and amide bond [223]. And lincosamides are currently widely used in veterinary clinical fields [224]. Resistance to lincosamide is generally divided into three categories: structural changes at the ribosome target site, active efflux, and enzymatic inactivation [225,226]. Bacteria resistance to lincosamide is due to changes in the protein composition of the 50S ribosomal subunit after a one-step chromosomal mutation, leading to high-level resistance [227]. The methylation of 23S ribosomal RNA, antibiotic modification by specific enzymes, or active bacterial efflux contributes to resistance against lincomycin and clindamycin [228]. Modification of ribosomal targets confers broad-spectrum resistance to lincosamides, whereas antibiotic efflux and inactivation only some of these molecules [229]. To date, a total of six genes associated with resistance to lincosamide have been discovered: lnu, cfr, erm, vga, lsa, and sal. These genes are frequently associated with mobile genetic elements (MGEs), such as plasmids, transposons, integrative and conjugative elements, genomic islands, and prophages [230].

The erm(A), erm(B), erm(C), erm(T), lnu(A), lnu(B), lnu(E) and lsa(E) genes have been detected in S. suis strains [231]. Among them, the erm(B) gene mediates resistance to lincosamide antibiotics by encoding ribosome methylation [232]. The erm(T) gene is located on the plasmid and integration and conjugation element (ICE) of S. suis strains, and the plasmid and ICE carrying the erm(T) gene facilitate its dissemination [233]. Mass spectrometry experiments showed that the novel lincosamide resistance gene lnu(E) can catalyze the nucleotidation of lincomycin [224]. lnu(B) (formerly linB) inactivates lincosamide antibiotics through adenylation, while the lsa(E) gene encodes an ABC transporter that generates resistance to lincosamide antibiotics by excreting the drug from the bacterium resistance [234].

12. Sulfonamides

Sulfonamides (SN) or sulfonamides, represent a significant category of synthetic antimicrobial agents that are extensively utilized in the medical field to combat bacterial infections in both humans and animals [144]. The SN structures are organo‑sulfur compounds containing -SO2NH2 and/or -SO2NH2 - group, characterized by the presence of a sulfanilamide group and a distinct 6 - or 5-membered heterocyclic rings [235]. The target of sulfonamides is dihydrotrexate synthetase (DHPS), encoded by the folP gene, in the folate pathway, which is also the basis of its selectivity [236]. The combination therapy of trimethoprim and sulfamethoxazole, which targets both dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), has proven effective in treating various common and specific clinical infections [237].

Resistance to sulfonamides arises via two primary mechanisms: folP mutations and/or the acquisition of heterologous sequence- divergent genes that encode DHPS variants insensitive to sulfanilamide [236]. DHPS with low affinity for sulfonamides are encoded on plasmids that have the potential for high-speed transfer to other organisms. In addition, sul1, sul2, and sul3 are known plasmid-encoded sulfonamides resistance genes that produce DHPs and induce resistance to sulfonamides [238]. Studies have revealed that the dhfr gene encoding S. suis dihydrofolate reductase (DHFR) was amplified from clarified lysate of S. suis P1/7 and S. suis HE06 [238]. The decreased sensitivity to trimethoprim was associated with mutations in the dhfr gene of S. suis and its promoter, along with the horizontal acquisition of transmissible trimethoprim-resistant dhfr genes [144,153].

13. Oxazolidinones

Oxazolidinones is a five-membered heterocyclic compound whose cyclic amide and ester have the same carbonyl group. Based on the reciprocal position of oxygen and nitrogen atoms in the five-membered ring, oxazolidinones can exist in various structural isomer forms [239]. These compounds inhibit bacterial protein synthesis by competitively binding to 23S rRNA in the catalytic site of the bacterial 50S ribosome [240]. Oxazolidinones are utilized extensively in both organic and medicinal chemistry, with notable examples including linezolid, tedizolid, and contezolid [241].

Resistance to oxazolidinones is caused by mutational changes, and the drugs inhibit protein synthesis by interacting with the A site of the bacterial ribosome, and interfering with the localization of aminoacyl-tRNA [196]. Currently, cfr and optrA have only been detected in S. suis, and optrA was mainly isolated [242,243]. And screening of the resistance mechanism of phosphorus resistant S. suis revealed that the optrA and cfr genes were present in 100 % and 2.4 % of isolates, respectively [132]. The resistance of S. suis to phenol-oxazolidinone (PhO) is increasing rapidly due to the transferable resistance gene optrA, which causes concern [243].

14. Pleuromutilin

For several decades, pleuromutilins have played a significant role in veterinary medicine. These antibiotics selectively targets and inhibits bacterial translation [244]. Pleuromutilins are semi-synthetic derivatives of the naturally occurring tricyclic diterpenoid known as pleuromutilin, named after the fungus Pleurotus mutilus that produces polystatin [245]. Key examples of these compounds include tiamulin and valnemulin [246]. Pleuropleins inhibit bacterial protein synthesis by binding to the central portion of the V domain of the 50S ribosome subunit of the peptidyl transferase center (PTC), preventing the CCA terminus of tRNAs from correctly locating for peptide transfer at the A- and p - sites, resulting in inhibitory peptide bond formation [247]. The distinctive mechanism through which pleuromutilins operate and their attachment to highly conserved sites on ribosomes reduces the likelihood of developing resistance. Additionally, there is a lack of cross-resistance with other classes of antibiotics, including those that inhibit protein synthesis, such as macrolides, ketolactones, and fusidic acid [248]. Although the incidence of pleuromutilins resistance is very low, there is still a cross-resistance mechanism.

Resistance to pleuromutilins can occur through modifications at the target site, enzymatic degradation of the antibiotic, and mechanisms that actively pump the drug out of the cell [247]. Examples include substitution of guanine at position 2032 in the 23S rRNA, binding of the drug to the 23S rRNA of the 50S subunit of the bacterial ribosome, and the use of broad-spectrum exporters [249] or specific transporters to evacuate the pleuromutilin drug from bacterial cells. Resistance to the drug pleuromutilin has been detected in ABC-F RPP variants Lsa(E) and Vga(F) in S. suis [169,250]. In addition, the cfr gene confers resistance to pleuromutilin as optrA, a more relevant determinant of S. suis AMR [251].

15. Conclusions and outlook

S. suis is a zoonotic disease with wide distribution, great harm, and a complex pathogenic mechanism. As S. suis becomes more resistant and the resistance mechanisms become increasingly complex, controlling S. suis in pigs has become increasingly challenging. Consequently, it is necessary to increase further the importance of the prevention and treatment of swine streptococcal disease. Implementing effective strategies to prevent and treat infections can help disrupt the transmission of S. suis, improve the efficiency of disease control in pigs, and foster better development within the pig farming industry.

There is an urgent need for a globally concerted response to address the development of novel antimicrobial compounds and strategies, as well as retarding the spread and further development of antimicrobial-resistant bacteria. The environment serves as a bridge between various animals and soil, water, sand and sewage. Trategies including source control of antibiotic misuse, advanced wastewater treatment, enhanced environmental surveillance, and adoption of eco-friendly technologies are essential. Essential measures include facilitating as well as speeding up the development, testing and approval of new antibiotics and novel drug development systems, and segregating different classes of antimicrobial compounds for human and animal use as far as is possible. Naturally, better efforts at infection control, surveillance and diagnostics are also important.

The “One Health” framework, emphasizing the interconnected health of humans, animals, and ecosystems, is pivotal in combating S. suis. By implementing scientific and reasonable prevention and control measures, not only can the harm of diseases to humans, animals and the environment be effectively reduced, but also the health and sustainable development of the ecosystem can be promoted. Global cooperation, as seen in WHO-FAO initiatives, strengthens surveillance and policy alignment across borders. By integrating veterinary science, human medicine, and environmental governance the One Health approach presents a comprehensive strategy to address the risks posed by S. suis, safeguarding health equity and sustainability for all interconnected domains.

CRediT authorship contribution statement

Fei Liu: Writing – review & editing, Writing – original draft, Investigation, Funding acquisition, Data curation, Conceptualization. Shuzhi Zhang: Writing – original draft, Visualization, Data curation, Conceptualization. Mihajlo Erdeljan: Writing – review & editing, Supervision. Yuyu Zhang: Writing – review & editing, Investigation. Zhi Chen: Writing – review & editing, Methodology, Investigation. Jianda Li: Writing – review & editing, Investigation, Data curation. Luogang Ding: Writing – review & editing, Software, Methodology. Lin Zhang: Writing – review & editing, Supervision, Software. Wenbo Sun: Writing – review & editing, Visualization, Investigation. Jiang Yu: Writing – review & editing, Supervision, Methodology, Conceptualization. Jiaqiang Wu: Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.