Cross-resistance among kanamycin, capreomycin and viomycin have been reported since the studies performed by Tsukamura and Mizuno. 111 Several other studies have also reported cross-resistance between kanamycin and amikacin or between kanamycin and capreomycin or viomycin to variable degrees. 112,113 The most common molecular mechanism of drug resistance has been associated with an A1401G. Although PZA resistance in M. tuberculosis was shown by McDermott’s group to be related to loss of nicotinamidase and pyrazinamidase in 1967 , the mechanism of PZA resistance was not known until 1996 when mutation in the pncA gene encoding nicotinamidase and pyrazinamidase was demonstrated to cause PZA resistance. pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada. Antimicrob Agents Chemother 44: 528–532. [PubMed] [CrossRef] The recognized mechanism of resistance to ethambutol has been linked to mutations in the gene embB with mutations at position embB306 as the most prevalent in most of the studies performed [47,48]. Some studies, however, have also found mutations in embB306 in ethambutol susceptible isolates [49]. Ethambutol has poor CSF penetration, even in the setting of inflammation. 198,203,204 Ethambutol primarily is used as the fourth drug when there is a possibility of resistance to other first-line drugs. 3.1.2 Mechanism of resistance Because INH is the most commonly used antituberculosis drug, resistance to INH occurs more frequently among clinical isolates than re sistance to any other agent (Karakousis 2009). Overview on mechanisms of isoniazid action and resistance in. the mechanism of resistance is due to the acquisition of mutations in katG. In vitro mutagenesis experiments of the katG gene have confirmed these observations (Heym et al., 1999). 3.1.1. Role of katG gene mutations in isoniazid-resistance. Mutations in the katG gene play a very prominent role in mediating INH resistance. The. M. tuberculosis resistance to ethambutol is due to random spontaneous genetic mutations, occurring at a rate of approximately 1 in 10 7 organisms. Mutations most commonly result in increased production of the enzyme arabinosyl transferase, which overwhelms the inhibitory effects of ethambutol [ 2,3 ]. Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated. An alternative mechanism of resistance is through Arr-catalyzed ADP-ribosylation of rifampicin. With the assistance of the enzyme Arr produced by the pathogen Mycobacterium smegmatis , ADP-ribose is added to rifampicin at one of its ansa chain hydroxy groups, thereby inactivating the drug.