Characterization of In Vitro Resistance to Linezolid in Mycobacterium abscessus

Single-step selection of Mycobacterium abscessus mutants resistant to linezolid yielded high-level resistance at a low frequency that was associated with mutations in 23S rRNA or the ribosomal protein L3. Surprisingly, linezolid-resistant rRNA mutations conferred cross-resistance to several unrelate...

Full description

Saved in:
Bibliographic Details
Published inMicrobiology spectrum Vol. 11; no. 4; p. e0219923
Main Authors Negatu, Dereje A, Aragaw, Wassihun Wedajo, Dartois, Véronique, Dick, Thomas
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 17.08.2023
Subjects
cross resistance
MAB_4384
MmpL5-MmpS5
nontuberculous mycobacteria
NTM
TetR
rplC
MmpL5-MmpS5
NTM
cross resistance
TetR
nontuberculous mycobacteria
rrl
MAB_4384
oxazolidinones
Online AccessGet full text

Cover

More Information
Summary:Single-step selection of Mycobacterium abscessus mutants resistant to linezolid yielded high-level resistance at a low frequency that was associated with mutations in 23S rRNA or the ribosomal protein L3. Surprisingly, linezolid-resistant rRNA mutations conferred cross-resistance to several unrelated antibiotics. Low-level linezolid-resistant mutants were isolated at a higher frequency and were due to loss-of-function mutations in the transcriptional regulator MAB_4384, the repressor of the drug efflux pump MmpL5-MmpS5. The protein synthesis inhibitor linezolid is used for the treatment of lung disease caused by Mycobacterium abscessus. However, many strains of the bacterium show poor susceptibility to the antibiotic. For most clinical isolates, resistance is not due to mutations in the target of the drug, the ribosome. The mechanism responsible for non-target-related, indirect linezolid resistance is unknown. Here, we analyzed the development of linezolid resistance in the M. abscessus reference strain . We found, as expected, resistance mutations in the ribosome. In addition, we identified mutations in a system that involves a drug pump, suggesting drug efflux as a mechanism of resistance to linezolid. This finding may inform the analysis of clinical resistance to linezolid. Surprisingly, a subset of linezolid-resistant ribosome mutations conferred cross-resistance to several structurally and mechanistically unrelated drugs, uncovering a novel multidrug resistance mechanism.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
The authors declare no conflict of interest.
ISSN:2165-0497
2165-0497
DOI:10.1128/spectrum.02199-23