Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all β-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with β-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin-binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models shows that penicillin/β-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for ‘susceptible’ MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin but the absence of clavulanic acid, which suggests that penicillin/β-lactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.
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We thank L. R. Hansen Kildevang and A. Medina for testing of the Danish isolates. We thank É. Brouillette and F. Malouin for providing isolates. This work was supported by Medical Research Council partnership grants (G1001787/1 and MR/N002660/1) held between the Department of Veterinary Medicine and School of Clinical Medicine at the University of Cambridge, the Moredun Research Institute and the Wellcome Sanger Institute. This publication presents independent research supported by the Health Innovation Challenge Fund (WT098600 and HICF-T5-342)—a parallel funding partnership between the Department of Health and Wellcome Trust. The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health or Wellcome Trust. E.M.H. is supported by a UK Research and Innovation Fellowship (MR/S00291X/1). F.C. is supported by the Wellcome Trust (201344/Z/16/Z). X.B. is supported by a UK–China AMR Partnership Grant (MR/P007201/1).
C.U.K. is a consultant for the World Health Organization Regional Office for Europe, QuantuMDx Group and Foundation for Innovative New Diagnostics, which involves work for Cepheid, Hain Lifescience and the World Health Organization. C.U.K. is an advisor to GenoScreen. The European Society of Mycobacteriology awarded C.U.K. the Gertrud Meissner Award, which is sponsored by Hain Lifescience. The Bill and Melinda Gates Foundation, Janssen Pharmaceutica and PerkinElmer covered C.U.K.’s travel and accommodation to enable presentations at meetings. The Global Alliance for TB Drug Development and Otsuka Novel Products have supplied C.U.K. with antibiotics for in vitro research. C.U.K. has collaborated with Illumina on a number of scientific projects. S.J.P. and J.P. are consultants to Next Gen Diagnostics. S.J.P. is a consultant to Specific Technologies. All other authors have no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–7, Tables 2 and 6–8, Supplementary Discussion, Supplementary References, and footnotes for Supplementary Tables 1 and 3–5.
Key features of 110 MRSA isolates screened for β-lactam resistance.
Key features of 298 MRSA isolates screened for penicillin–clavulanic acid susceptibility.
Key features of Danish clinical isolates screened for penicillin–clavulanic acid susceptibility.
Relevant characteristics of CC8 and USA300 included in Fig. 4b.