Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria
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Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria. / Maurer, Florian P.
in: J ANTIMICROB CHEMOTH, Jahrgang 70, Nr. 5, 05.2015, S. 1412-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria
AU - Maurer, Florian P
N1 - © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PY - 2015/5
Y1 - 2015/5
N2 - OBJECTIVES: Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clinically available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. We investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus.METHODS: Clinical isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2', 3' and 4' of ring 1 in MIC assays. Cell-free extracts of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2')-Id(+)], EP10 [aac(2')-Id(-)] and SZ461 [aac(2')-Id(+), rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatography (TLC). Cell-free ribosome translation assays were performed to directly study drug-target interaction.RESULTS: Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2'-hydroxy-AGA as compared with 2'-amino-AGA, indicating that an aminoglycoside-2'-acetyltransferase, Aac(2'), contributes to innate AGA susceptibility. TLC experiments confirmed enzymatic activity consistent with Aac(2'). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis.CONCLUSIONS: Our findings point to AME as important determinants of AGA susceptibility in M. abscessus.
AB - OBJECTIVES: Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clinically available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. We investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus.METHODS: Clinical isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2', 3' and 4' of ring 1 in MIC assays. Cell-free extracts of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2')-Id(+)], EP10 [aac(2')-Id(-)] and SZ461 [aac(2')-Id(+), rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatography (TLC). Cell-free ribosome translation assays were performed to directly study drug-target interaction.RESULTS: Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2'-hydroxy-AGA as compared with 2'-amino-AGA, indicating that an aminoglycoside-2'-acetyltransferase, Aac(2'), contributes to innate AGA susceptibility. TLC experiments confirmed enzymatic activity consistent with Aac(2'). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis.CONCLUSIONS: Our findings point to AME as important determinants of AGA susceptibility in M. abscessus.
KW - Acetyltransferases
KW - Aminoglycosides
KW - Anti-Bacterial Agents
KW - Biotransformation
KW - Humans
KW - Microbial Sensitivity Tests
KW - Mycobacterium Infections, Nontuberculous
KW - Nontuberculous Mycobacteria
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1093/jac/dku550
DO - 10.1093/jac/dku550
M3 - SCORING: Journal article
C2 - 25604746
VL - 70
SP - 1412
EP - 1419
JO - J ANTIMICROB CHEMOTH
JF - J ANTIMICROB CHEMOTH
SN - 0305-7453
IS - 5
ER -
