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Mutations in the gdpP gene are a clinically relevant mechanism for β-lactam resistance in meticillin-resistant Staphylococcus aureus lacking mec determinants.

ABSTRACT: In Staphylococcus aureus, resistance to β-lactamase stable β-lactam antibiotics is mediated by the penicillinbinding protein 2a, encoded by mecA or by its homologues mecB or mecC. However, a substantial number of meticillin-resistant isolates lack known mec genes and, thus, are called meticillin resistant lacking mec (MRLM). This study aims to identify the genetic mechanisms underlying the MRLM phenotype. A total of 141 MRLM isolates and 142 meticillin-susceptible controls were included in this study. Oxacillin and cefoxitin minimum inhibitory concentrations were determined by broth microdilution and the presence of mec genes was excluded by PCR. Comparative genomics and a genome-wide association study (GWAS) approach were applied to identify genetic polymorphisms associated with the MRLM phenotype. The potential impact of such mutations on the expression of PBP4, as well as on cell morphology and biofilm formation, was investigated. GWAS revealed that mutations in gdpP were significantly associated with the MRLM phenotype. GdpP is a phosphodiesterase enzyme involved in the degradation of the second messenger cyclic-di-AMP in S. aureus. A total of 131 MRLM isolates carried truncations, insertions or deletions as well as amino acid substitutions, mainly located in the functional DHH-domain of GdpP. We experimentally verified the contribution of these gdpP mutations to the MRLM phenotype by heterologous complementation experiments. The mutations in gdpP had no effect on transcription levels of pbp4; however, cell sizes of MRLM strains were reduced. The impact on biofilm formation was highly strain dependent. We report mutations in gdpP as a clinically relevant mechanism for β-lactam resistance in MRLM isolates. This observation is of particular clinical relevance, since MRLM are easily misclassified as MSSA (meticillin-susceptible S. aureus), which may lead to unnoticed spread of β-lactam-resistant isolates and subsequent treatment failure.

SUBMITTER: Sommer A

PROVIDER: S-EPMC8715439 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The role of general practitioners (GPs) as reservoir and potential source for Staphylococcus aureus (SA) transmission is unknown. Our primary objective was to evaluate the prevalence of SA and community-acquired methicillin resistant SA (CA-MRSA) carrier status (including spa typing) among GPs and their patients in Belgium. The secondary objective was to determine the association between SA/CA-MRSA carriage in patients and their characteristics, SA carriage in GPs, GP and practice characteristics.The Belgian GPs, who swabbed their patients in the APRES study (which assessed the prevalence of SA nasal carriage in nine European countries; November 2010 -June 2011), were asked to swab themselves as well (May-June 2011). GPs and their patients had to complete a questionnaire on factors related to SA carriage and transmission. SA isolation including CA-MRSA and spa typing was performed on the swabs.In eighteen practices 34 GPs swabbed patients of which 25 GPs provided personal swabs. The analysis was performed on 3008 patient records. Among GPs SA carriage (28%) was more prevalent than among their patients (19.2%), but CA-MRSA carriage was not present. SA was more prevalent among younger patients and those living with cattle. Spa typing SA and MRSA strains did not suggest correlation within practices or between patients and GPs, but chronic skin conditions of GPs and always handshaking patients by SA positive GPs were associated with more SA among patients, and hand washing after every patient contact with less SA among patients in practices with high antibiotic prescribing rates.No MRSA was found among GPs, although their SA carriership was higher compared to their patients'. Spa types did not cluster within practices, possibly due to difference in timing of swabbing. To minimise SA transmission to their patients GPs should consider taking appropriate care of their chronic skin diseases, antibiotic prescribing behaviour, handshaking and hand washing habits.

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Mutations in the gdpP gene are a clinically relevant mechanism for β-lactam resistance in meticillin-resistant Staphylococcus aureus lacking mec determinants.

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