The NaHCO-Responsive Phenotype in Methicillin-Resistant Staphylococcus Aureus (MRSA) Is Influenced by Genotype

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2022 May 16

PMID 35575577

Authors

Selvi C Ersoy

Adhar C Manna

Richard A Proctor

Henry F Chambers

Ewan M Harrison

Arnold S Bayer

Ambrose Cheung

Affiliations

Soon will be listed here.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) strains are a leading cause of many invasive clinical syndromes, and pose treatment difficulties due to their resistance to most β-lactams on standard laboratory testing. A novel phenotype frequently identified in MRSA strains, termed 'NaHCO-responsiveness', is a property whereby strains are susceptible to many β-lactams in the presence of NaHCO. Specific genotypes, repression of /PBP2a expression and perturbed maturation of PBP2a by NaHCO have all been associated with this phenotype. The aim of this study was to define the relationship between specific genotypes and PBP2a substitutions, on the one hand, with NaHCO-responsiveness . Mutations were made in the ribosomal binding site (RBS -7) and at amino acid position 246 of its coding region in parental strains MW2 (NaHCO-responsive) and C36 (NaHCO- nonresponsive) to generate 'swap' variants, each harboring the other's -RBS/coding region genotypes. Successful swaps were confirmed by both sequencing, as well as predicted swap of penicillin-clavulanate susceptibility phenotypes. MW2 swap variants harboring the nonresponsive genotypes became NaHCO-nonresponsive (resistant to the β-lactam, oxacillin [OXA]), in the presence of NaHCO. Moreover, these swap variants had lost NaHCO-mediated repression of /PBP2a expression. In contrast, C36 swap variants harboring the NaHCO-responsive genotypes remained NaHCO-nonresponsive phenotypically, and still exhibited nonrepressible /PBP2a expression. These data demonstrate that in addition to the genotype, NaHCO-responsiveness may also depend on strain-specific genetic backgrounds.

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References

Murakami K, Nomura K, Doi M, Yoshida T . Production of low-affinity penicillin-binding protein by low- and high-resistance groups of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1987; 31(9):1307-11. PMC: 174932. DOI: 10.1128/AAC.31.9.1307. View

Zhuang H, Zhu F, Lan P, Ji S, Sun L, Chen Y . A random forest model based on core genome allelic profiles of MRSA for penicillin plus potassium clavulanate susceptibility prediction. Microb Genom. 2021; 7(9). PMC: 8715440. DOI: 10.1099/mgen.0.000610. View

Murray R . Staphylococcus aureus infective endocarditis: diagnosis and management guidelines. Intern Med J. 2005; 35 Suppl 2:S25-44. DOI: 10.1111/j.1444-0903.2005.00978.x. View

Otero L, Rojas-Altuve A, Llarrull L, Carrasco-Lopez C, Kumarasiri M, Lastochkin E . How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A. 2013; 110(42):16808-13. PMC: 3800995. DOI: 10.1073/pnas.1300118110. View

Ersoy S, Chambers H, Proctor R, Rosato A, Mishra N, Xiong Y . Impact of Bicarbonate on PBP2a Production, Maturation, and Functionality in Methicillin-Resistant (MRSA). Antimicrob Agents Chemother. 2021; 65(5). PMC: 8092911. DOI: 10.1128/AAC.02621-20. View

Hartman B, Tomasz A . Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. J Bacteriol. 1984; 158(2):513-6. PMC: 215458. DOI: 10.1128/jb.158.2.513-516.1984. View

Kumaraswamy M, Lin L, Olson J, Sun C, Nonejuie P, Corriden R . Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR Stenotrophomonas maltophilia. J Antimicrob Chemother. 2016; 71(5):1264-9. PMC: 4830416. DOI: 10.1093/jac/dkv487. View

Hiramatsu K, Katayama Y, Yuzawa H, Ito T . Molecular genetics of methicillin-resistant Staphylococcus aureus. Int J Med Microbiol. 2002; 292(2):67-74. DOI: 10.1078/1438-4221-00192. View

Lin L, Nonejuie P, Munguia J, Hollands A, Olson J, Dam Q . Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens. EBioMedicine. 2015; 2(7):690-8. PMC: 4534682. DOI: 10.1016/j.ebiom.2015.05.021. View

10.

Oliveira D, de Lencastre H . Methicillin-resistance in Staphylococcus aureus is not affected by the overexpression in trans of the mecA gene repressor: a surprising observation. PLoS One. 2011; 6(8):e23287. PMC: 3149077. DOI: 10.1371/journal.pone.0023287. View

11.

Fishovitz J, Rojas-Altuve A, Otero L, Dawley M, Carrasco-Lopez C, Chang M . Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics. J Am Chem Soc. 2014; 136(28):9814-7. PMC: 4210145. DOI: 10.1021/ja5030657. View

12.

Ersoy S, Heithoff D, Barnes 5th L, Tripp G, House J, Marth J . Correcting a Fundamental Flaw in the Paradigm for Antimicrobial Susceptibility Testing. EBioMedicine. 2017; 20:173-181. PMC: 5478264. DOI: 10.1016/j.ebiom.2017.05.026. View

13.

Chen F, Wang C, Chen C, Hsu Y, Wang K . Role of the mecA gene in oxacillin resistance in a Staphylococcus aureus clinical strain with a pvl-positive ST59 genetic background. Antimicrob Agents Chemother. 2013; 58(2):1047-54. PMC: 3910894. DOI: 10.1128/AAC.02045-13. View

14.

Harrison E, Ba X, Coll F, Blane B, Restif O, Carvell H . Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus. Nat Microbiol. 2019; 4(10):1680-1691. PMC: 7611363. DOI: 10.1038/s41564-019-0471-0. View

15.

Cassat J, Thomsen I . Staphylococcus aureus infections in children. Curr Opin Infect Dis. 2021; 34(5):510-518. PMC: 8630804. DOI: 10.1097/QCO.0000000000000752. View

16.

Murakami K, Tomasz A . Involvement of multiple genetic determinants in high-level methicillin resistance in Staphylococcus aureus. J Bacteriol. 1989; 171(2):874-9. PMC: 209677. DOI: 10.1128/jb.171.2.874-879.1989. View

17.

Hiramatsu K, Ito T, Tsubakishita S, Sasaki T, Takeuchi F, Morimoto Y . Genomic Basis for Methicillin Resistance in Staphylococcus aureus. Infect Chemother. 2013; 45(2):117-36. PMC: 3780952. DOI: 10.3947/ic.2013.45.2.117. View

18.

Saiman L, OKeefe M, Graham 3rd P, Wu F, Said-Salim B, Kreiswirth B . Hospital transmission of community-acquired methicillin-resistant Staphylococcus aureus among postpartum women. Clin Infect Dis. 2003; 37(10):1313-9. DOI: 10.1086/379022. View

19.

Ersoy S, Hanson B, Proctor R, Arias C, Tran T, Chambers H . Impact of Bicarbonate-β-Lactam Exposures on Methicillin-Resistant (MRSA) Gene Expression in Bicarbonate-β-Lactam-Responsive vs. Non-Responsive Strains. Genes (Basel). 2021; 12(11). PMC: 8619011. DOI: 10.3390/genes12111650. View

20.

Edwards B, Andini R, Esposito S, Grossi P, Lew D, Mazzei T . Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?. J Glob Antimicrob Resist. 2016; 2(3):133-140. DOI: 10.1016/j.jgar.2014.03.009. View