Molecular genetics of Mycobacterium tuberculosis resistant to aminoglycosides and cyclic peptide capreomycin antibiotics in Korea

Abstract

Aminoglycosides are key drugs for the treatment of multidrug-resistant tuberculosis. A total of 97 extensively drug-resistant (XDR) and 29 pan-susceptible Mycobacterium tuberculosis isolates from Korean tuberculosis patients were analyzed to characterize mutations within the rrs, rpsL, gidB, eis and tlyA genes. Thirty (56.6 %) of the 53 streptomycin (STR)-resistant strains had a rpsL mutation and eight strains (15.1 %) had a rrs (514 or 908 site) mutation, whereas 11 (20.8 %) of the 53 STR-resistant strains had a gidB mutation without rpsL or either rrs mutation. Most of the gidB mutations conferred low-level STR resistance, and 22 of these mutations were novel. Mutation at position 1401 in rrs lead to resistance to kanamycin (80/95 = 84.2 %; KAN), amikacin (80/87 = 92.0 %; AMK), and capreomycin (74/86 = 86.0 %; CAP). In this study, 13.7 % (13/95) of KAN-resistant strains showed eis mutations, including 4 kinds of novel mutations. Isolates with eis structural gene mutations were cross-resistant to STR, KAN, CAP, and AMK. Here, 5.8 % (5/86) of the CAP-resistant strains harbored a tlyA mutation that included 3 different novel point mutations. Detection of the A1401G mutation appeared to be 100 % specific for the detection of resistance to KAN and AMK. These data establish the presence of phenotypic XDR strains using molecular profiling and are helpful to understanding of aminoglycoside resistance at the molecular level.

Multidrug-Resistant Nontuberculous Mycobacteria Isolated from Cystic Fibrosis Patients

“…The same was observed for patients C and H. The mechanisms for the acquisition of NTM resistance to amikacin are unknown. Nevertheless, mutations in specific regions of the rrs and rpsL genes may confer aminoglycoside resistance in mycobacteria (26,27,28).…”

Disparities in Capreomycin Resistance Levels Associated with the rrs A1401G Mutation in Clinical Isolates of Mycobacterium tuberculosis

“…Studies on the contribution of each mutation to specific cross-resistance patterns are variable. Of particular concern is the discordant relationship between the most common rrs mutation, A1401G, and CAP resistance, as this mutation is often found in clinical isolates determined to be CAP susceptible by the agar proportion method of DST (3,7,9,[12][13][14][15][16][17][18]. Despite these discrepancies, the presence of the A1401G allele is considered a strong predictor of cross-resistance to all three injectable second-line drugs (4,17,19).…”

“…As all three drugs share the same molecular target and bind to a similar location on the ribosome, cross-resistance is frequently observed (3,(7)(8)(9). Cross-resistance is highly associated with mutations mapping to the 16S rRNA (rrs) sequence, most notably, the A1401G, C1402T, and G1484T mutations (7,(10)(11)(12). Studies on the contribution of each mutation to specific cross-resistance patterns are variable.…”

Molecular Basis of Drug Resistance in Mycobacterium tuberculosis

“…While rpsL is an essential gene, nonsynonymous mutations are tolerated for ribosomal function but result in reduced aminoglycoside binding. Common mutations in aminoglycoside resistance that confer resistance to STR are RpsL K43R and K88R (79,80).…”

“…While the Eis protein is capable of acetylating AMK, its affinity for AMK is low, and studies of clinical isolates with eis promoter-up mutations reveal selective KAN resistance with relative preservation of AMK susceptibility (83). Nevertheless, clinical isolates with eis mutations that are KAN-and AMKresistant have been described (79), so the specificity of eis mutations for KAN resistance remains uncertain.…”