Dabul Andrei Nicoli Gebieluca, Avaca-Crusca Juliana Sposto, Van Tyne Daria, Gilmore Michael S, Camargo Ilana Lopes Baratella Cunha
1 Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo , São Carlos, Brazil .
2 Department of Ophthalmology, Harvard Medical School , Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
Microb Drug Resist. 2018 Jun;24(5):519-526. doi: 10.1089/mdr.2017.0279. Epub 2017 Oct 17.
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.
一株对替加环素敏感（TGC-S）的序列型（ST）5临床耐甲氧西林金黄色葡萄球菌（MRSA）菌株在逐步增加的替加环素浓度中培养，产生了耐药性提高八倍的突变体。对它们的基因组进行测序以鉴定导致耐药性的基因改变。还研究了通常与替加环素耐药性相关的rpsJ中的改变。替加环素耐药性由转录阻遏物mepR的功能丧失突变介导，导致外排泵mepA的去阻遏。通过mepA自身的连续突变获得了更高水平的耐药性。在选定的菌株中未观察到RpsJ的改变，但我们在TGC-S临床菌株中观察到先前与耐药性相关的K57M替换。因此，CC5 MRSA体外对替加环素耐药的途径似乎是由于mepR功能丧失突变导致mep操纵子去阻遏，随后是MepA外排泵的改变。这表明除了rpsJ突变之外，其他进化途径也可导致CC5 MRSA产生替加环素耐药性。
