Making Sense of MRSA Mechanisms without mec

June 28, 2018

Nearly 90% of methicillin-resistant Staphylococcus aureus (MRSA) disease is caused by 1 of 6 circulating S. aureus strain carrying a mec gene. PBP proteins create the peptidoglycan cross links that strengthen the bacterial cell wall; the mec alleles encode PBPs with low affinity for the β-lactam drug that binds this protein target. This makes the majority of MRSA cases easy to screen by molecular testing. But what about the remaining MRSA cases? 

In a new Antimicrobial Agents and Chemotherapy report, scientists investigated and categorized the diverse genetic causes of non-mec-associated MRSA infections in a National Reference Center for S. aureus. If only a few mutations lead to resistance, these might be categorized and also screened by molecular means. They discovered that many different mutations lead to non-mec MRSA.

AACJournal: Genetic Diversity among Staphylococcus aureusIsolates Showing Oxacillin and/or Cefoxitin Resistance Not Linked to the Presence of mecGenes.

The research team, led by first author M. Angeles Argudin and senior scientist Oliver Denis, identified 32 isolates of methicillin-resistant lacking mec (MRLM) S. aureus strains out of a collection of 298. All isolates had been collected in Belgium between 2013 and 2015 and were tested for mutations that are known to confer β-lactam resistance.

12 of these 32 isolates were β-Lactamase positive by penicillin disk diffusion test. These β-lactamase hyperproducers (BHP) break down the drug before it can reach its target; these strains may be successfully treated with degradation-resistant β-lactams like oxacillin, or a combination of β-lactam and β-lactamase inhibitor. The remaining 20 isolates had diverse genetic explanations for their resistance that defied a single categorization and were scattered among many different S. aureus lineages, including both hospital-associated and livestock-associated lineages.

The non-BHP group with diverse genetic explanations for the MRSA phenotype were referred to as modified S. aureus (MODSA). Most of the mutations in the MODSA group were in one of the native PBP genes, which altered the enzyme active sites. Other mutations included overexpression of one of the PBP genes, especially pbp4, the overexpression of which is associated with methicillin resistance. 12 of the 20 MODSA also had mutations within gdpP, a gene responsible for controlling regulating c-di-AMP levels that influence many biological processes, including cell wall architecture and tolerance to β-lactam drugs. Importantly, gdpP mutation can increase PBP4 levels, which leads to subsequent methicillin resistance.

In this study, slightly over 10% of the samples tested representing MLRM strains, but this may not be an accurate representation, since the strains deposited were those that had been difficult to diagnose for β-lactam resistance. This diverse group included β-lactamase hyperproducers, MODSA, and combinations of genetic mutations (both BHP and MODSA). Detecting methicillin resistance is made more complex since an infection can carry multiple subpopulations, one resistant and one susceptible (a phenomenon known as ‘heteroresistance’); understanding the genetic basis for various drug resistance mechanisms may lead to better diagnostic tests to pinpoint drug resistance profiles of clinical isolates, improving patient treatment. 

Author: Julie Wolf

Julie Wolf
Dr. Julie Wolf is in science communications at Indie Bio, and was a former ASM employee. Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.