Long-range DHPS mutations unexpectedly increase Mycobacterium chimaera susceptibility to sulfonamides.

Autor: Gotthard G; Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France., Muhammed Ameen S; Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France., Drancourt M; Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France. Electronic address: michel.drancourt@univmed.fr., Chabriere E; Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France.
Jazyk: angličtina
Zdroj: Journal of global antimicrobial resistance [J Glob Antimicrob Resist] 2013 Dec; Vol. 1 (4), pp. 181-188. Date of Electronic Publication: 2013 Aug 01.
DOI: 10.1016/j.jgar.2013.05.003
Abstrakt: The two closely related mycobacteria, Mycobacterium intracellulare and Mycobacterium chimaera, exhibit a more than two-fold difference in their in vitro susceptibility to sulfonamides. Sulfonamides are antibiotics targeting the 6-hydroxymethyl-7,8-dihydropteroate synthase (DHPS) enzyme involved in the folate synthesis pathway. Comparing the DHPS gene sequence in six M. intracellulare and M. chimaera types trains and clinical isolates yielded only four amino acid changes. In silico structural modelling surprisingly indicated that these amino acids are not located in the active site of DHPS and do not interact directly with sulfonamides. Unexpectedly, these amino acids in distal positions may play a key role in the increased sulfonamide susceptibility observed in M. chimaera compared with M. intracellulare. This example illustrates how three-dimensional models could help to identify distal mutations capable of modulating enzymatic activity.
(Copyright © 2013 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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