Molecular basis underlying Mycobacterium tuberculosis D-cycloserine resistance. Is there a role for ubiquinone and menaquinone metabolic pathways?
BACKGROUND
Tuberculosis remains a formidable threat to global public health. Multidrug-resistant tuberculosis presents increasing burden on the control strategy. D-Cycloserine (DCS) is an effective second-line drug against Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis. Though less potent than isoniazid (INH) and streptomycin, DCS is crucial for antibiotic-resistant tuberculosis. One advantage of DCS is that less drug-resistant M. tuberculosis is reported in comparison with first-line antituberculosis drugs such as INH and rifampin.


METHODS
In this review, we summarise our current knowledge of DCS, and review the drug target and low-level resistance of DCS in M. tuberculosis. We summarise the metabolism of D-alanine (D-Ala) and peptidoglycan biosynthesis in bacteria. We first compared the amino acid similarity of Mycobacterium alanine racemase and D-Ala:D-alanine ligase and quite unexpectedly found that the two enzymes are highly conserved among Mycobacterium.


CONCLUSIONS
We summarise the drug targets of DCS and possible mechanisms underlying its low-level resistance for the first time. One significant finding is that ubiquinone and menaquinone metabolism-related genes are novel genes underlying DCS resistance in Escherichia coli and with homologues in M. tuberculosis. Further understanding of DCS targets and basis for its low-level resistance might inspire us to improve the use of DCS or find better drug targets.
Southwest University, Institute of Modern Biopharmaceuticals, School of Life Sciences, State Key Laboratory Breeding Base of Eco-Enviroment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education , Beibei, Chongqing 400715 , China +86 23 68367 108 ; +86 23 68367 108 ; jianpingxiefudan@gmail.com.
Weiling
W
Hong
Lifang
L
Chen
Jianping
J
Xie
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D003523:Cycloserine / Q000378:metabolism / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010457:Peptidoglycan / Q000096:biosynthesis; D014451:Ubiquinone / Q000378:metabolism*; D024482:Vitamin K 2 / Q000378:metabolism*
D010457:Peptidoglycan; D024482:Vitamin K 2; D014451:Ubiquinone; D003523:Cycloserine; D000409:Alanine
D-cycloserine; Mycobacterium tuberculosis; drug resistance; drug target