Affiliation:
1. AstraZeneca India Private Limited, Bellary Road, Hebbal, Bangalore 560024, India
Abstract
ABSTRACT
Efflux systems are important in determining the efficacy of antibiotics used in the treatment of bacterial infections. In the last decade much attention has been paid to studying the efflux pumps of mycobacteria. New classes of compounds are under investigation for development into potential candidate drugs for the treatment of tuberculosis. Quite often, these have poor bactericidal activities but exhibit excellent target (biochemical) inhibition. Microarray studies conducted in our laboratories for deciphering the mode of action of experimental drugs revealed the presence of putative ABC transporters. Among these transporters, Rv1218c was chosen for studying its physiological relevance in mediating efflux in
Mycobacterium tuberculosis
. A Δ
Rv1218c
mutant of
M. tuberculosis
displayed a 4- to 8-fold increase in the inhibitory and bactericidal potency for different classes of compounds. The MICs and MBCs were reversed to wild-type values when the full-length
Rv1218c
gene was reintroduced into the Δ
Rv1218c
mutant on a multicopy plasmid. Most of the compound classes had significantly better bactericidal activity in the Δ
Rv1218c
mutant than in the wild-type H37Rv, suggesting the involvement of
Rv1218c
gene product in effluxing these compounds from
M. tuberculosis
. The implication of these findings on tuberculosis drug discovery is discussed.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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