Dingle Yu
Danchun Guo1
Yuejie Zheng- 1Shenzhen Children’s Hospital, Shenzhen, China
- 2Microbiology Laboratory, National Center for Children’s Health, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Beijing, China
With the widespread use of antibiotics, antimicrobial resistance (AMR) has become a global problem that endangers public health. Despite the global high prevalence of group A Streptococcus (GAS) infections and the global widespread use of β-lactams, β-lactams remain the first-line treatment option for GAS infection. β-hemolytic streptococci maintain a persistent susceptibility to β-lactams, which is an extremely special phenomenon in the genus Streptococci, while the exact current mechanism is not known. In recent years, several studies have found that the gene encoding penicillin binding protein 2X (pbp2x) is associated with GAS with reduced-β-lactam susceptibility. The purpose of this review is to summarize the current published data on GAS penicillin binding proteins and β-lactam susceptibility, to explore the relationship between them, and to be alert to the emergence of GAS with reduced susceptibility to β-lactams.
Introduction
Group A Streptococcus (GAS), also known as Streptococcus pyogenes (S. pyogenes), is a very important human pathogen. With the widespread use of antibiotics, the incidence of GAS infection has decreased considerably, but it remains an important human pathogen, ranking in the top 10 causes in terms of morbidity and mortality of infectious diseases (Bessen et al., 2019), responsible for more than 700 million infection,1.8 million severe infections and 517,000 deaths worldwide each year (Carapetis et al., 2005; Ralph and Carapetis, 2013). Importantly, so far, there is no licensed vaccine to prevent GAS infections (Steer et al., 2016). GAS can cause a wide range of clinical conditions, from mild pharyngitis to life-threatening invasive infections (Brockmann et al., 2018; Lamagni et al., 2018; Liu et al., 2018).
According to the World Health Organization (World Health Organization, 2014), antimicrobial resistance (AMR) is a global challenge that poses a serious threat to public health and the world economy. In 2014, the WHO Global Antimicrobial Resistance Surveillance System (GLASS) released the first global report on AMR surveillance (World Health Organization, 2014). β-lactams are the of first-line antibiotics of choice for the treatment of most GAS infections. An anomaly in the biology of S. pyogenes is the persistent high susceptibility to β-lactams. To date, no naturally occurring penicillin-resistant strain in S. pyogenes has been identified (Horn et al., 1998; Suzuki et al., 2015; Chochua et al., 2017; Yu et al., 2020; Yu et al., 2021b). This is unusual because resistance to β-lactams has emerged independently several times in many other important Gram-positive human bacterial pathogens(Zapun et al., 2008). Resistance to β-lactams in Streptococcus pneumoniae, an important example of a Streptococcal pathogen, has been described globally. While rare, Streptococcus agalactiae (group B Streptococcus [GBS]) and Streptococcus dysgalactiae subspecies equisimilis (SDSE) reported pbp2x point mutations resulting in reduced susceptibility to β-lactams (Dahesh et al., 2008; Fuursted et al., 2016; Metcalf et al., 2017). In recent years, reduced-penicillin-susceptibility of GAS has been reported (Kimura et al., 2008; Metcalf et al., 2017). As previously observed in other streptococci, the emergence of mutations in certain PBP genes is considered a first step towards potential full penicillin resistance, and warrants continued surveillance (Jamin et al., 1993; Kimura et al., 2008; Hayes et al., 2020b).
Interpretation criteria for antimicrobial susceptibility testing results of GAS to β-lactams
The Clinical and Laboratory Standards Institute (CLSI) and the European Commission on Antimicrobial Susceptibility Testing (EUCAST) guidelines are widely recognized and have long recommended penicillin for the treatment of GAS infections. There are no “intermediate” or “resistant” breakpoints to penicillin according to CLSI or EUCAST guideline. According to CLSI criteria, whose criteria have remained unchanged for many years, a minimum inhibition zone ≥24mm or a minimum inhibitory concentration (MIC)≤0.12 μg/mL for β-hemolytic streptococci indicates susceptibility to penicillin, and also to other β-lactams (amoxicillin, ampicillin and cefaclor).However, there have been some reports of GAS isolates being described as “non-susceptible” or “resistant” to β-lactams (Amábile-Cuevas et al., 2001; Capoor et al., 2006; Ogawa et al., 2011; Berwal et al., 2018). After reviewing these papers, we found that the terms “intermediate” or “resistant” used in these reports were not used accurately for interpretation of results (Yu et al., 2020; Yu et al., 2021b). The authors of these papers should have described the isolates as “non-susceptible” but instead referred to them as “intermediate” or “resistant”, while CLSI and EUCAST do not define breakpoints for these terms for GAS. Therefore, highlighting the current lack of understanding of GAS susceptibility breakpoints and interpretation for β-lactam antibiotics by many researchers.
Penicillin and other β-lactams
β-lactam antibiotics, including penicillin, are a class of antibiotic molecules that disrupt bacterial cell walls during cell proliferation. They are fungal, natural or synthetic antimicrobial agents (Fleming, 1929; Sheehan and Henery-Logan, 1959). There are five classes of penicillin antibiotics including natural penicillins, aminopenicillins, penicillins resistant to penicillinase, extended-spectrum penicillins and aminopenicillin/β-lactamase inhibitor combinations (Miller, 2002). Other antibiotics also have typical β-lactam ring structures, including cephalosporins, carbapenems and monoamides, which together with penicillin are known as β-lactam antibiotics.
After the introduction of penicillin in the early 1940s, Staphylococci and enterococci (Miller et al., 2014) developed resistance within just a few years (Kirby, 1944; Lakhundi and Zhang, 2018). From the mid-1960s to the 1970s, intermediate strains of Streptococcus pneumoniae were sporadically reported (Hansman et al., 1974; Jacobs et al., 1979; Klugman, 1990). While still rare, from the mid-1990s, reports of reduced susceptibility to GBS has been documented (Kimura et al., 2008; Gaudreau et al., 2010). GBS strains with reduced susceptibility to β-lactams are been described in Japan and the United States (Dahesh et al., 2008; Seki et al., 2015; Kobayashi et al., 2021). SDSE is the species most closely related to GAS (Oppegaard et al., 2017). During 2010 to 2012, four incidents of penicillin-resistant (PR) SDSE isolated from blood cultures of three patients were detected in Denmark (Fuursted et al., 2016).
However, there are exceptions. A key exception to Fleming ‘s warning about the relationship between antimicrobial use and the development of resistance is the persistent susceptibility of GAS to β-lactam antibiotics (Horn et al., 1998). Eighty years after the introduction of penicillin, GAS strains still maintain consistent susceptibility to various β-lactams, and even the MICs of GAS to β-lactams remain low and stable (Yu et al., 2021a). The reasons for the persistent susceptibility of GAS to β-lactams are unclear, but may include differences in the rate and mechanism of horizontal gene transfer between GAS and other Streptococci.
Mechanism of resistance
There are three main mechanisms of resistance to β-lactams, including destruction of the antibiotic by β-lactamases, reduced affinity for PBP binding, or reduced access to PBPs (Ambler, 1980). Resistance of Gram-positive organisms to β-lactams is mainly due to target modifications, in which PBPs undergo structural changes (Fisher and Mobashery, 2016). Reduced susceptibility to penicillin in GAS has been demonstrated due to amino acid substitutions within PBPs that affect the ability to bind penicillins (Jamin et al., 1993; Kimura et al., 2008; Hayes et al., 2020b).
Mutations within PBPs
Identification and subsequent genetic analysis of antimicrobial resistant strains revealed that resistant strains have chimeric high molecular mass penicillin-binding proteins (HMM PBPs) compared to susceptible strains (Zighelboim and Tomasz, 1980; Dowson et al., 1989). In resistant Streptococci, the evolution from penicillin susceptible to reduced susceptibility and then to non-susceptible occurs through the progressive accumulation of amino acid substitutions in HMM PBPs rather than through single-event horizontal gene transfer of β-lactamase or low β-lactam affinity HMM PBPs (Zighelboim and Tomasz, 1980; Barcus et al., 1995; Kimura et al., 2008; Zapun et al., 2008; Fuursted et al., 2016). Thus, the identification of the genetic polymorphism in pathogenic streptococci leading to reduced antibiotic susceptibility has been observed from phenotype to genotype. This phenotype-to-genotype workflow has dominated the molecular basis of antibiotic resistance research for decades and is responsible for the discovery of novel mechanisms. GAS with reduced susceptibility to β-lactams have acquired mutations in genes encoding PBPs, including PBP1a, PBP2a, PBP2b and PBP2x. Some mutations have been identified, but the most common mutation in the GAS results in the substitution of amino acid in PBP2x transpeptidase for T553K (Vannice et al., 2020; Chochua et al., 2022) (Table 1).
Table 1 Reports of reduced susceptibility to β-lactams amongst group A Streptococcus isolates and the associated amino acid substitutions identified.
Prevalence of GAS with reduced-β-lactam susceptibility
All reports of GAS with reduced-β-lactam susceptibility worldwide to date are detailed in Table 1. Detailed characterization of GAS with reduced β-lactams susceptibility were first reported in 2001 (Amábile-Cuevas et al., 2001). Since then, it has also been reported in India (Capoor et al., 2006; Berwal et al., 2018), Japan (Ogawa et al., 2011; Ikeda et al., 2021), in Iceland(Southon et al., 2020) and in the United States (Musser et al., 2020; Vannice et al., 2020; Chochua et al., 2022).
In 2020, Hayes et al. investigated the relative frequency of PBP sequence variations in 9,667 S. pyogenes isolates worldwide (Hayes et al., 2020a). The majority of these genomic sequences were derived from UK and US datasets that focused on invasive diseases (Ben Zakour et al., 2015; Davies et al., 2015; Athey et al., 2016; Chalker et al., 2017; Chochua et al., 2017; Kapatai et al., 2017; Turner et al., 2017; Bergin et al., 2018; Coelho et al., 2019; Davies et al., 2019; Dickinson et al., 2019; Lynskey et al., 2019). They found that mutations in S. pyogenes PBPs occured rarely in this global database, with less than 3 amino acid changes differing in more than 99% of the world population. Only 4 of 9 667 strains contained mutations near the active sites of PBP2x or PBP1a transpeptidase. No reported PBP2x T553K mutation was found. Their findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence that such mutations become fixed in the S. pyogenes population or that mutations in the PBPs are being sequentially acquired. However, because low levels of resistance to subclinical lactams could theoretically confer a biological advantage to GAS, vigilance in monitoring population GAS for PBP mutations is encouraged (Musser et al., 2020).
In 2022, Beres et al. (Beres et al., 2022) analyzed 26,465 S. pyogenes genome sequences. Population genomic data identified amino acid changes in PBP1a, 1b, 2a, and 2x. The evolutionary signature of these proteins under positive selection is a potential candidate for reduced susceptibility to β-lactams. In 2022, Olsen et al. (Olsen et al., 2022) again noted that whole genome sequencing identified a GAS strain containing a chimeric PBP2x derived from an SDSE recombinant fragment. The results suggest that mutations such as PBP2x chimeras may lead to reduced susceptibility to β-lactams and increased fitness and virulence.
Hanage et al. (Hanage and Shelburne, 2020) noted that studies have shown that mutations of PBP are associated with reduced susceptibility of S. pneumoniae to β-lactam antibiotics (Li et al., 2016), Streptococcus agalactiae (Dahesh et al., 2008a), some SDSE(Fuursted et al., 2016) and GAS (Vannice et al., 2020).In another study (Musser et al., 2020), two related Streptococcus pyogenes strains with reduced susceptibility to ampicillin, amoxicillin, and cefotaxime, antibiotics commonly used to treat S. pyogenes infections, were reported. The two strains had the same nonsynonymous (amino acid-substituting) mutation in the pbp2x gene, encoding penicillin- binding protein 2X (PBP2X). They identified 137 strains that together had 37 nonsynonymous mutations in 36 codons of pbp2x. The authors propose that GAS with reduced susceptibility to β-lactams associated with mutations in the pbp2x gene are geographically widespread. Does this study suggest that we are finally at the beginning of the era of widespread susceptibility of GAS to β-lactams? They believed that this answer is no (Hanage and Shelburne, 2020).
Summary
Currently, penicillin, the first-line treatment of GAS infection, is generally considered effective for GAS. However, reports of reduced susceptibility to β-lactams are becoming more common. For now, clinicians can continue to be confident that β-lactams remain the agents of choice for the treatment of GAS infections. The fluctuating nature of the emergence of GAS strains, including those with reduced susceptibility to various antimicrobials, means that ongoing surveillance of the GAS population is both in the public health interest and helps clinicians understand the changing nature of medically important bacteria.
Author contributions
YZ and YY proposed the topic of this review. DY and DG conducted a literature search and wrote this review. YZ and YY revised and edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by Guangdong High-level Hospital Construction Fund, the Project of the Expert Committee on Clinical Application and Drug Resistance Evaluation of Antimicrobial Drugs of the National Health Commission (KJYWZWH-OT-02-2021-06), Shenzhen Key Medical Discipline Construction Fund (SZXK032), and Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012).
Conflict of interest
The authors indicated that this study was conducted without any commercial or financial relationships that could be interpreted as potential conflicts of interest.
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References
Amábile-Cuevas, C. F., Hermida-Escobedo, C., Vivar, R.l. (2001). Comparative in vitro activity of moxifloxacin by e-test against Streptococcus pyogenes. Clin. Infect. Dis. 32 (Suppl 1), S30–S32. doi: 10.1086/319373
Ambler, R. (1980). The structure of beta-lactamases. Trans. R Soc. Lond B Biol. Sci. 289 (1036), 321–331. doi: 10.1098/rstb.1980.0049
Athey, T., Teatero, S., Sieswerda, L., Gubbay, J., Marchand-Austin, A., Li, A., et al. (2016). High incidence of invasive group a streptococcus disease caused by strains of uncommon emm types in thunder bay, Ontario, Canada. J. Clin. Microbiol. 54 (1), 83–92. doi: 10.1128/jcm.02201-15
Barcus, V. A., Ghanekar, K., Yeo, M., Coffey, T. J., Dowson, C. G. (1995). Genetics of high level penicillin resistance in clinical isolates of Streptococcus pneumoniae. FEMS Microbiol. Lett. 126 (3), 299–303. doi: 10.1111/j.1574-6968.1995.tb07433.x
Ben Zakour, N. L., Davies, M. R., You, Y., Chen, J. H. K., Forde, B. M., Stanton-Cook, M., et al. (2015). Transfer of scarlet fever-associated elements into the group a streptococcus M1T1 clone. Sci. Rep. 5 (15877), 1–7. doi: 10.1038/srep15877
Beres, S. B., Zhu, L., Pruitt, L., Olsen, R. J., Faili, A., Kayal, S., et al. (2022). Integrative reverse genetic analysis identifies polymorphisms contributing to decreased antimicrobial agent susceptibility in streptococcus pyogenes. mBio 13 (1), e03618–e03621. doi: 10.1128/mbio.03618-21
Bergin, S. M., Balamurugan, P., Timothy, B., Choon, C. H., Ming, M. Y., Sheng, F., et al. (2018). An outbreak of streptococcus pyogenes in a mental health facility advantage of well-timed whole-genome sequencing over emm typing. Infection Control Hosp. Epidemiol. 39 (7), 852–860. doi: 10.1017/ice.2018.101
Berwal, A., Chawla, K., Shetty, S., Gupta, A. (2018). Trend of antibiotic susceptibility of Streptococcus pyogenes isolated from respiratory tract infections in tertiary care hospital in south Karnataka. Iran J. Microbiol. 11 (1), 13–18.
Bessen, D. E., Smeesters, P. R., Beall, B. W. (2019). Molecular epidemiology, ecology, and evolution of group a streptococci. Microbiol. Spect 6 (5), 177–203. doi: 10.1128/9781683670131.ch12
Brockmann, S., Eichner, L., Eichner, M. (2018). Constantly high incidence of scarlet fever in Germany. Lancet Infect. Dis. 18 (5), 499–500. doi: 10.1016/s1473-3099(18)30210-x
Capoor, M. R., Nair, D., Deb, M., Batra, K., Aggarwal, P. (2006). Resistance to erythromycin and rising penicillin MIC in streptococcus pyogenes in India. Jpn J. Infect. Dis. 59 (5), 334–336. doi: 10.1097/01.qai.0000246035.86135.c0
Carapetis, J. R., Steer, A. C., Mulholland, E. K., Weber, M. (2005). The global burden of group a streptococcal diseases. Lancet Infect. Dis. 5 (11), 685–694. doi: 10.1016/S1473-3099(05)70267-X
Chalker, V., Jironkin, A., Coelho, J., Al-Shahib, A., Platt, S., Kapatai, G., et al. (2017). Genome analysis following a national increase in scarlet fever in England 2014. BMC Genomics 18 (1), 224. doi: 10.1186/s12864-017-3603-z
Chochua, S., Metcalf, B., Li, Z., Mathis, S., Tran, T., Rivers, J., et al. (2022). Invasive group a streptococcal penicillin binding protein 2X variants associated with reduced susceptibility to β-lactam antibiotics in the united states 2015–2021. Antimicrob. Agents Chemother. 66 (9), 1–14. doi: 10.1128/aac.00802-22
Chochua, S., Metcalf, B. J., Li, Z., Rivers, J., Mathis, S., Jackson, D., et al. (2017). Population and whole genome sequence based characterization of invasive group a streptococci recovered in the united states during 2015. MBio 8 (5), e01422-01417. doi: 10.1128/mBio.01422-17
Coelho, J. M., Kapatai, G., Jironkin, A., Al-Shahib, A., Daniel, R., Dhami, C., et al. (2019). Genomic sequence investigation streptococcus pyogenes clusters in england, (2010–2015). Clin. Microbiol. Infect. 25 (1), 96–101. doi: 10.1016/j.cmi.2018.04.011
Dahesh, S., Hensler, M. E., Van Sorge, N. M., Gertz, R. E., Jr., Schrag, S., Nizet, V., et al. (2008). Point mutation in the group b streptococcal pbp2x gene conferring decreased susceptibility to beta-lactam antibiotics. Antimicrob. Agents Chemother. 52 (8), 2915–2918. doi: 10.1128/AAC.00461-08
Davies, M. R., Holden, M. T., Coupland, P., Chen, J. H. K., Venturini, C., Barnett, T. C., et al. (2015). Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance. Nat. Genet. 47 (1), 84–87. doi: 10.1038/ng.3147
Davies, M. R., McIntyre, L., Mutreja, A., Lacey, J. A., Lees, J. A., Towers, R. J., et al. (2019). Atlas of group a streptococcal vaccine candidates compiled using large-scale comparative genomics. Nat. Genet. 51 (6), 1035–1043. doi: 10.1038/s41588-019-0417-8
Dickinson, H., Reacher, M., Nazareth, B., Eagle, H., Fowler, D., Underwood, A., et al. (2019). Whole-genome sequencing in the investigation of recurrent invasive group a streptococcus outbreaks in a maternity unit. J. Hosp Infect. 101 (3), 320–326. doi: 10.1016/j.jhin.2018.03.018
Dowson, C. G., Hutchison, A., Brannigan, J. A., George, R. C., Hansman, D., Liñares, J., et al. (1989). Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc. Natl. Acad. Sci. 86 (22), 8842–8846. doi: 10.1073/pnas.86.22.8842
Fisher, J. F., Mobashery, S. (2016). β-lactam resistance mechanisms: Gram-positive bacteria and mycobacterium tuberculosis. Cold Spring Harbor Perspect. Med. 6 (5), a025221. doi: 10.1101/cshperspect.a025221
Fleming, A. (1929). On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 10 (3), 226.
Fuursted, K., Stegger, M., Hoffmann, S., Lambertsen, L., Andersen, P. S., Deleuran, M., et al. (2016). Description and characterization of a penicillin-resistant streptococcus dysgalactiae subsp. equisimilis clone isolated from blood in three epidemiologically linked patients. J. Antimicrob. Chemother. 71 (12), 3376–3380. doi: 10.1093/jac/dkw320
Gaudreau, C., Lecours, R., Ismaïl, J., Gagnon, S., Jetté, L., Roger, M. (2010). Prosthetic hip joint infection with a streptococcus agalactiae isolate not susceptible to penicillin G and ceftriaxone. J. Antimicrob. Chemother. 65 (3), 594–595. doi: 10.1093/jac/dkp458
Hanage, W. P., Shelburne, A. S. (2020). Streptococcus pyogenes with reduced susceptibility to beta-lactams: how big an alarm bell? Clin. Infect. Dis. 71 (1), 205–206. doi: 10.1093/cid/ciz1006
Hansman, D., Devitt, L., Miles, H., Riley, I. (1974). Pneumococci relatively insensitive to penicillin in Australia and new Guinea. Med. J. Aust. 2 (10), 353–356. doi: 10.5694/j.1326-5377.1974.tb70836.x
Hayes, A., Lacey, J. A., Morris, J. M., Davies, M. R., Tong, S. Y. C., Limbago, B. M. (2020a). Restricted sequence variation in streptococcus pyogenes penicillin binding proteins. mSphere 5 (2), e00090-20. doi: 10.1128/mSphere.00090-20
Hayes, K., O'Halloran, F., Cotter, L. (2020b). A review of antibiotic resistance in group b Streptococcus: the story so far. Crit. Rev. Microbiol. 46 (3), 253–269. doi: 10.1080/1040841X.2020.1758626
Horn, D. L., Zabriskie, J. B., Austrian, R., Cleary, P. P., Ferretti, J. J., Fischetti, V. A., et al. (1998). Why have group a streptococci remained susceptible to penicillin? report on a symposium. Clin. Infect. Dis., 26(6), 1341–1345. doi: 10.1086/516375
Ikeda, T., Suzuki, R., Jin, W., Wachino, J.-i., Arakawa, Y., Kimura, K. (2021). Isolation of group a streptococci with reduced in vitro β-lactam susceptibility harboring amino acid substitutions in penicillin-binding proteins in Japan. Antimicrob. Agents Chemother. 65 (12), e01482–e01421. doi: 10.1128/AAC.01482-21
Jacobs, M., Mithal, Y., Robins-Browne, R., Gaspar, M., Koornhof, H. (1979). Antimicrobial susceptibility testing of pneumococci: determination of Kirby-Bauer breakpoints for penicillin G, erythromycin, clindamycin, tetracycline, chloramphenicol, and rifampin. Antimicrob. Agents Chemother. 16 (2), 190–197. doi: 10.1128/AAC.16.2.190
Jamin, M., Hakenbeck, R., Frere, J.-M. (1993). Penicillin binding protein 2x as a major contributor to intrinsic β-lactam resistance of Streptococcus pneumoniae. FEBS Lett. 331 (1-2), 101–104. doi: 10.1016/0014-5793(93)80305-E
Kapatai, G., Coelho, J., Platt, S., Chalker, V. J. (2017). Whole genome sequencing of group a Streptococcus: development and evaluation of an automated pipeline for emmgene typing. PeerJ 5, e3226. doi: 10.7717/peerj.3226
Kimura, K., Suzuki, S., Wachino, J., Kurokawa, H., Yamane, K., Shibata, N., et al. (2008). First molecular characterization of group b streptococci with reduced penicillin susceptibility. Antimicrob. Agents Chemother. 52 (8), 2890–2897. doi: 10.1128/AAC.00185-08
Kirby, W. M. (1944). Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science 99 (2579), 452–453. doi: 10.1126/science.99.2579.452
Klugman, K. P. (1990). Pneumococcal resistance to antibiotics. Clin. Microbio Rev. 3 (2), 171–196. doi: 10.1128/CMR.3.2.171
Kobayashi, M., McGee, L., Chochua, S., Apostol, M., Alden, N. B., Farley, M. M., et al. (2021). “Low but increasing prevalence of reduced beta-lactam susceptibility among invasive group b streptococcal isolates, US population-based surveillance 1998–2018,” in Open forum infectious diseases (US: Oxford University Press), ofaa634.
Lakhundi, S., Zhang, K. (2018). Methicillin-resistant Staphylococcus aureus: molecular characterization, evolution, and epidemiology. Clin. Microbio Rev. 31 (4), e00020–e00018. doi: 10.1128/CMR.00020-18
Lamagni, T., Guy, R., Chand, M., Henderson, K. L., Chalker, V., Lewis, J., et al. (2018). Resurgence of scarlet fever in england 2014–16: a population-based surveillance study. Lancet Infect. Dis. 18 (2), 180–187. doi: 10.1016/s1473-3099(17)30693-x
Li, Y., Metcalf, B., Chochua, S., Li, Z., Gertz, R., Walker, H., et al. (2016). Penicillin-binding protein transpeptidase signatures for tracking and predicting β-lactam resistance levels in streptococcus pneumoniae. mBio 7 (3), e00756–e00716. doi: 10.1128/mBio.00756-16
Liu, Y., Chan, T., Yap, L., Luo, Y., Xu, W., Qin, S., et al. (2018). Resurgence of scarlet fever in China: a 13-year population-based surveillance study. Lancet Infect. Dis. 18 (8), 903–912. doi: 10.1016/s1473-3099(18)30231-7
Lynskey, N. N., Jauneikaite, E., Li, H. K., Zhi, X., Turner, C. E., Mosavie, M., et al. (2019). Emergence of dominant toxigenic M1T1 streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological study. Lancet Infect. Dis. 19 (11), 1209–1218. doi: 10.1016/s1473-3099(19)30446-3
Metcalf, B., Chochua, S., Gertz, J. R., Hawkins, P., Ricaldi, J., Li, Z., et al. (2017). Short-read whole genome sequencing for determination of antimicrobial resistance mechanisms and capsular serotypes of current invasive Streptococcus agalactiae recovered in the USA. Clin. Microbiol. Infect. 23 (8), 574.e577–574.e514. doi: 10.1016/j.cmi.2017.02.021
Miller, E. L. (2002). The penicillins: a review and update. J. Midwifery Womens Health 47 (6), 426–434. doi: 10.1016/S1526-9523(02)00330-6
Miller, W. R., Munita, J. M., Arias, C. A. (2014). Mechanisms of antibiotic resistance in enterococci. Expert Rev. Anti Infect. Ther. 12 (10), 1221–1236. doi: 10.1586/14787210.2014.956092
Musser, J. M., Beres, S. B., Zhu, L., Olsen, R. J., Vuopio, J., Hyyryläinen, H.-L., et al. (2020). Reduced in vitro susceptibility of Streptococcus pyogenes to beta-lactam antibiotics associated with mutations in the pbp2x gene is geographically widespread. J. Clin. Microbiol. 58 (4), e01993–e01919. doi: 10.1128/JCM.01993-19
Ogawa, T., Terao, Y., Sakata, H., Okuni, H., Ninomiya, K., Ikebe, K., et al. (2011). Epidemiological characterization of streptococcus pyogenes isolated from patients with multiple onsets of pharyngitis. FEMS Microbiol. Lett. 318 (2), 143–151. doi: 10.1111/j.1574-6968.2011.02252.x
Olsen, R. J., Zhu, L., Mangham, R. E., Faili, A., Kayal, S., Beres, S. B., et al. (2022). A chimeric penicillin binding protein 2X significantly decreases in vitro beta-lactam susceptibility and increases in vivo fitness of streptococcus pyogenes. Am. J. Pathol. 192 (10), 1397–1406. doi: 10.1016/j.ajpath.2022.06.011
Olsen, R. J., Zhu, L., Musser, J. M. (2020). A single amino acid replacement in penicillin-binding protein 2x in streptococcus pyogenes significantly increases fitness on subtherapeutic benzylpenicillin treatment in a mouse model of necrotizing myositis. Am. J. Pathol. 190 (8), 1625–1631. doi: 10.1016/j.ajpath.2020.04.014
Oppegaard, O., Mylvaganam, H., Skrede, S., Lindemann, P. C., Kittang, B. R. (2017). Emergence of a streptococcus dysgalactiae subspecies equisimilis stG62647-lineage associated with severe clinical manifestations. Sci. Rep. 7 (1), 1–10. doi: 10.1038/s41598-017-08162-z
Ralph, A. P., Carapetis, J. R. (2013). Group a streptococcal diseases and their global burden. Curr. Top. Microbiol. Immunol. 368, 1–2. doi: 10.1007/82_2012_280
Seki, T., Kimura, K., Reid, M. E., Miyazaki, A., Banno, H., Jin, W., et al. (2015). High isolation rate of MDR group b streptococci with reduced penicillin susceptibility in Japan. J. Antimicrob. Chemother. 70 (10), 2725–2728. doi: 10.1093/jac/dkv203
Sheehan, J. C., Henery-Logan, K. R. (1959). The total synthesis of penicillin V. J. Am. Chem. Soc. 81 (12), 3089–3094. doi: 10.1021/ja01521a044
Southon, S., Beres, S., Kachroo, P., Saavedra, M., Erlendsdóttir, H., Haraldsson, G., et al. (2020). Population genomic molecular epidemiological study of macrolide-resistant streptococcus pyogenes in iceland 1995To 2016: identification of a large clonal population with a pbp2x mutation conferring reduced in vitro β-lactam susceptibility. J. Clin. Microbiol. 58 (9), e00638–e00620. doi: 10.1128/jcm.00638-20
Steer, A. C., Carapetis, J. R., Dale, J. B., Fraser, J. D., Good, M. F., Guilherme, L., et al. (2016). Status of research and development of vaccines for Streptococcus pyogenes. Vaccine 34 (26), 2953–2958. doi: 10.1016/j.vaccine.2016.03.073
Suzuki, T., Kimura, K., Suzuki, H., Banno, H., Jin, W., Wachino, J.-i., et al. (2015). Have group a streptococci with reduced penicillin susceptibility emerged? J. Antimicrob. Chemother. 70 (4), 1258–1259. doi: 10.1093/jac/dku492
Turner, C. E., Bedford, L., Brown, N. M., Judge, K., Török, M. E., Parkhill, J., et al. (2017). Community outbreaks of group a streptococcus revealed by genome sequencing. Sci. Rep. 7 (1), 1–9. doi: 10.1038/s41598-017-08914-x
Vannice, K. S., Ricaldi, J., Nanduri, S., Fang, F. C., Lynch, J. B., Bryson-Cahn, C., et al. (2020). Streptococcus pyogenes pbp2x mutation confers reduced susceptibility to β-lactam antibiotics. Clin. Infect. Dis. 71 (1), 201–204. doi: 10.1093/cid/ciz1000
World Health Organization (2014). Antimicrobial resistance: global report on surveillance. Geneva, Switzerland: World Health Organization.
Yu, D., Liang, Y., Lu, Q., Meng, Q., Wang, W., Huang, L., et al. (2021a). Molecular characteristics of streptococcus pyogenes isolated from Chinese children with different diseases. Front. Microbiol. 12, 1–10. doi: 10.3389/fmicb.2021.722225
Yu, D., Yanmin, B., Jiaosheng, Z., Lu, Q., Huang, L., Shen, X., et al. (2021b). Errors in the antimicrobial susceptibility test of group a hemolytic streptococcus for β-lactam antibiotics. Chin. J. Lab. Med. 44 (2), 103–106. doi: 10.3760/cma.j.cn114452-20200914-00727
Yu, D., Zheng, Y., Yang, Y. (2020). Is there emergence of β-lactam antibiotic-resistant streptococcus pyogenes in China? Infect. Drug Resist. 13, 2323–2327. doi: 10.2147/IDR.S261975
Zapun, A., Contreras-Martel, C., Vernet, T. (2008). Penicillin-binding proteins and β-lactam resistance. FEMS Microbiol. Rev. 32 (2), 361–385. doi: 10.1111/j.1574-6976.2007.00095.x
Keywords: group A Streptococcus (GAS), Streptococcus pyogenes, antibiotic resistance, Penicillin binding protein, Pbp2x, reduced-penicillin susceptibility, β-lactam
Citation: Yu D, Guo D, Zheng Y and Yang Y (2023) A review of penicillin binding protein and group A Streptococcus with reduced-β-lactam susceptibility. Front. Cell. Infect. Microbiol. 13:1117160. doi: 10.3389/fcimb.2023.1117160
Received: 06 December 2022; Accepted: 21 March 2023;
Published: 31 March 2023.
Edited by:
Debdutta Bhattacharya, Regional Medical Research Center (ICMR), IndiaReviewed by:
Lesley McGee, Centers for Disease Control and Prevention (CDC), United StatesCopyright © 2023 Yu, Guo, Zheng and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yuejie Zheng, yuejiez@sina.com; Yonghong Yang, yyh628628@sina.com