title: Long-range DHPS mutations unexpectedly increase Mycobacterium chimaera susceptibility to sulfonamides.
abstract: 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.
authors.affiliation: Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gotthard
authors.affiliation: Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France.
authors.forename: Sirwan
authors.initials: S
authors.lastname: Muhammed Ameen
authors.affiliation: Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France. Electronic address: michel.drancourt@univmed.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Drancourt
authors.affiliation: Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, Inserm 1095, 13005 Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chabriere
keywords: DHPS; Enzyme; Modelling; Mycobacterium; Sulfonamide