analyses of isoniazid and streptomycin resistance-associated mutations in .

Multi-drug resistant tuberculosis is categorised by the World Health Organisation (WHO) as a public health crisis. techniques were used to probe the structural basis of resistance to isoniazid and streptomycin. Isoniazid resistance-associated mutations in InhA were predicted to reduce the binding affinity of NADH to InhA, without affecting INH-NAD (competitive-inhibitor) binding. Perturbation of the mutated residues was predicted (with the AlloSigMA server) to modulate the free energy of allosteric modulation of key binding site residues F41, F149, Y158 and W222. These results suggest that allosteric modulation of the protein structure may be key to the mechanism by which isoniazid resistance-associated mutations act. Mutations in the methyltransferase glucose-inhibited division gene B (GidB) are associated with streptomycin resistance. Molecular docking was carried out to predict the structure of the GidB bound to its substrate (s-adenosyl methionine). The effects of streptomycin resistance-associated mutations in GidB on protein stability and substrate binding were predicted (using SDM and mCSM-lig). All GidB mutants were predicted to disfavour SAM binding.