Current Status and Unusual Mechanism of Multiresistance in Mycobacterium tuberculosis

Abstract

TB is a deadly disease and MDR-TB is spreading even DOTS drug regime has rigorously maintained with at least ten new drugs like isoniazid, capreomycin, dapsone, linezolid, pyrazinamide, ethambutol and Beda quinolone apart from traditional drugs like rifampicin, streptomycin, amikacin and clarithromycin. Rifampicin inhibits RNA polymerase and mutations in rpo gene codons give resistance. Streptomycin inhibits protein synthesis and mutation of ribosomal proteins and rRNA genes give resistance but no strAB or mphA1-9 mdr genes reported in Mycobacterium. Bedaquiline kills M. tuberculosis by inhibition of the membrane-bound F1F0-ATP synthase complex. Ciprofloxacin and ofloxacin were replaced by moxifloxacin that binds to DNA gyrase inhibiting DNA replication and/or transcription and mutations of gyrA at position 90 and 94 and gyrB at position 74, 88 and 91 give resistance. Kanamycin and amikacin inhibit protein synthesis and mutation of rrs gene gives resistance. However, aac2’-Ic type acetylating enzymes have also been suggested for multi-resistance. Ethambutol interferes with the biosynthesis of arabinogalactan in the cell wall and embB gene mutation at position 306 gives resistance. ErmMT methyl transferase adds methyl group to 23S rRNA at A2058 giving resistance to azithromycin and clarithromycin where capreomycin or viomycin peptide antibiotics may be effective drug. Ethionamide is a derivative of isonicotinic acid inhibits mycolic acid synthesis disrupting membrane function. Ethionamide resistance were linked due to mutations in etaA, ethA, ethR and inhA genes. Isoniazid is also a pro-drug and katG gene (S315T) mutation was reported for its resistance. Pyrazinamide after conversion to pyrazinoic acid disrupts membrane function inhibiting ATP synthesis and pncA or rpsA gene mutation likely gives resistance. Cycloserine is a peptidoglycan synthesis inhibitor competing D-Alanine ligase. We find beta-lactamase (BlaC) and penicillin binding protein (penA) as well as well studied emrB and qacB drug efflux proteins by genome wide search. But no 50-500 kb MDR plasmid carrying five or more mdr genes as found in most Enterobacteriaceae, have not sequenced in M. tuberculosis. We conclude that search for Mycobacterium plasmids must be accelerated pointing multi-resistance. Surely, phage therapy and gene medicines also have got momentum to overcome multi-resistance and antibiotics void.