Publication Date:
2018-01-30
Description:
Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistantMycobacterium tuberculosis(Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of theMtbETC with the purpose of defining their role and essentiality inMtb. Each NADH dehydrogenase was deleted in both virulent and BSL2-approvedMtbstrains, from which the double knockouts ΔndhΔnuoANand ΔndhAΔnuoANwere constructed. The ΔndhΔndhAdouble knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required forMtbgrowth. Δndhand ΔndhΔnuoANshowed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA,ΔnuoAN, and ΔndhAΔnuoANwere similar to the parental strain. Interestingly, although ΔnuoANhad no phenotype in vivo, ΔndhΔnuoANwas the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase ofMtband that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.
Print ISSN:
0027-8424
Electronic ISSN:
1091-6490
Topics:
Biology
,
Medicine
,
Natural Sciences in General
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