Resistance inIn VitroSelected Tigecycline-Resistant Methicillin-ResistantStaphylococcus aureusSequence Type 5 Is Driven by Mutations inmepRandmepAGenes

Abstract

A tigecycline-susceptible (TGC-S) Sequence Type (ST) 5 clinical methicillin-resistant Staphylococcus aureus (MRSA) strain was cultured in escalating levels of tigecycline, yielding mutants eightfold more resistant. Their genomes were sequenced to identify genetic alterations, resulting in resistance. Alterations in rpsJ, commonly related to tigecycline resistance, were also investigated. Tigecycline resistance was mediated by loss-of-function mutations in the transcriptional repressor mepR, resulting in derepression of the efflux pump mepA. Increased levels of resistance were obtained by successive mutations in mepA itself. No alterations in RpsJ were observed in selected strains, but we observed a K57M substitution, previously correlated with resistance, among TGC-S clinical strains. Thus, the pathway to tigecycline resistance in CC5 MRSA in vitro appears to be derepression of mep operon as the result of mepR loss-of-function mutation, followed by alterations in MepA efflux pump. This shows that other evolutionary pathways, besides mutation of rpsJ, are available for evolving tigecycline resistance in CC5 MRSA.

Streptomyces as a Prominent Resource of Future Anti-MRSA Drugs

“…Studies have reported MRSA to have overexpression of efflux pump through the mutations of both mep R and mep A genes resulting in overexpression of mep A and derepression of mep R. Furthermore, studies have shown the mutation of the ribosomal protein at S10 (Argudín et al, 2018 ). Study by Dabul et al ( 2018 ) found out that mutation in rpsJ was not observed in their MRSA strain studied, but only the efflux mechanism was determined (Dabul et al, 2018 ). Interestingly, tigecycline resistance is not associated with fitness cost as compared with daptomycin (Dabul et al, 2018 ).…”

“…Study by Dabul et al ( 2018 ) found out that mutation in rpsJ was not observed in their MRSA strain studied, but only the efflux mechanism was determined (Dabul et al, 2018 ). Interestingly, tigecycline resistance is not associated with fitness cost as compared with daptomycin (Dabul et al, 2018 ).…”

Eravacycline susceptibility was impacted by genetic mutation of 30S ribosome subunits, and branched-chain amino acid transport system II carrier protein, Na/Pi cotransporter family protein in Staphylococcus aureus

“…Our previous data indicated that tet(K) was frequently detected in MSSA with Erava MIC ≥0.5mg/L and it's still unknown whether tet(K) participated in the Erava heteroresistance or resistance [7]. The reduced susceptibility to Tige have been widely explained by the emergent mutations in genes encoding several 30S ribosome subunits, including 16S rRNA and 30S ribosome protein S10 [8][9][10][11][12][13][14][15][16][17]. The clinical significance of the genetic mutations of 30S ribosome subunits remains elusive should be further studied.…”

MarR family proteins are important regulators of clinically relevant antibiotic resistance

“…Methicillin-resistant Staphylococcus aureus (MRSA) is a well-publicized and high priority public health threat. 41 Yet, another underlying driver of multidrug-resistant S. aureus is the increased expression of mepA, which encodes a MATE family efflux pump; the expression of which is repressed by the MarR family member, MepR. 42,43 For instance, tigecycline-resistant MRSA strains appear to require mutations in mepR and mepA.…”