Mutation of
            <i>tlyA</i>
            Confers Capreomycin Resistance in
            <i>Mycobacterium tuberculosis</i>

Maus, Courtney E.; Plikaytis, Bonnie B.; Shinnick, Thomas M.

doi:10.1128/aac.49.2.571-577.2005

Cited by 202 publications

(172 citation statements)

References 42 publications

(51 reference statements)

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“…Levels of cross-resistance depended on the exact SNPs in each strain, with at least one strain appearing cross-resistant to CM as well as KM and AK (19). In a study of 18 CM-resistant mutants selected in vitro by transposition, an rRNA methyltransferase encoded by tlyA was implicated in CM resistance, with 4 of these isolates retaining full susceptibility to KM and AK (20). More recently, polymorphisms in gidB, another rRNA methyltransferase, were found to be closely associated with low-level SM resistance (20).…”

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confidence: 99%

Polymorphisms Associated with Resistance and Cross-Resistance to Aminoglycosides and Capreomycin in Mycobacterium tuberculosis Isolates from South Korean Patients with Drug-Resistant Tuberculosis

et al. 2010

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The aminoglycosides streptomycin, amikacin, and kanamycin and the cyclic polypeptide capreomycin are all widely used in second-line therapy for patients who develop multidrug-resistant tuberculosis. We have characterized a set of 106 clinical isolates of Mycobacterium tuberculosis using phenotypic drug susceptibility testing (DST) to determine the extent of resistance to each agent and cross-resistance between agents. These results were compared with polymorphisms in the DNA sequences of ribosome-associated genes previously implicated in resistance and with the clinical outcomes of subjects from whom these isolates were obtained. Thirty-six (34%) of these isolates displayed resistance to one or more of these agents, and the majority of these (20 of 36) showed cross-resistance to one or more agents. Most (33 of 36) of the resistant isolates showed polymorphisms in the 16S ribosome components RpsL and rrs. Three resistant strains (3 of 36) were identified that had no known polymorphisms in ribosomal constituents. For kanamycin and streptomycin, molecular DST significantly outperformed phenotypic DST using the absolute concentration method for predicting 4-month sputum conversion (likelihood ratios of 4.0 and 2.0, respectively) and was equivalent to phenotypic DST using the National Committee for Clinical Laboratory Standards (NCCLS)-approved agar proportion method for estimating MIC (likelihood ratio, 4.0). These results offer insight into mechanisms of resistance and crossresistance among these agents and suggest that the development of rapid molecular tests to distinguish polymorphisms would significantly enhance clinical utility of this important class of second-line antituberculosis drugs.Drug-resistant tuberculosis (TB) is an emerging issue in global TB control, with multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease threatening to overwhelm existing initiatives (8). The difference between MDR TB (resistant to at least isoniazid [INH] and rifampin [RIF]) and XDR TB (MDR plus resistant to any fluoroquinolone and at least one of the injectable second-line drugs amikacin [AK], kanamycin [KM], and capreomycin [CM]) is often life or death for patients suffering from drug-resistant TB (7,14,15). Nonetheless, the diagnosis of MDR and XDR TB remains a lengthy, technically demanding laboratory procedure relying on culturing bacteria isolated from patient sputum on solid or liquid medium in the presence of individual drugs. To make matters worse, such highly resistant strains occasionally show growth differences in in vitro culture that may be related to fitness costs imposed by the mutations conferring resistance (9). These growth differences, and the complexity of in vitro assessment of drug resistance, result in laboratory determinations of XDR of questionable reliability (16). There is a growing movement toward molecular drug susceptibility testing using a variety of detection platforms that show robust performance for the firstline agents that define MDR TB (10).Molecular drug susceptibility t...

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Polymorphisms Associated with Resistance and Cross-Resistance to Aminoglycosides and Capreomycin in Mycobacterium tuberculosis Isolates from South Korean Patients with Drug-Resistant Tuberculosis

et al. 2010

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“…Like RsmG and KsgA, which methylate the base moiety of 16S rRNA, TlyA, encoded by the tlyA gene, methylates the ribose moiety of nucleotide C1409 of 16S rRNA and C1920 of 23S rRNA in Mycobacterium tuberculosis (14,16). Inactivation of the tlyA gene confers low-level resistance to the ribosometargeting drug capreomycin, which has been used as a secondline antibiotic for tuberculosis chemotherapy.…”

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Inactivation of KsgA, a 16S rRNA Methyltransferase, Causes Vigorous Emergence of Mutants with High-Level Kasugamycin Resistance

Ochi

Kim

Tanaka

et al. 2009

Antimicrob Agents Chemother

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The methyltransferases RsmG and KsgA methylate the nucleotides G535 (RsmG) and A1518 and A1519 (KsgA) in 16S rRNA, and inactivation of the proteins by introducing mutations results in acquisition of low-level resistance to streptomycin and kasugamycin, respectively. In a Bacillus subtilis strain harboring a single rrn operon (rrnO), we found that spontaneous ksgA mutations conferring a modest level of resistance to kasugamycin occur at a high frequency of 10 ؊6 . More importantly, we also found that once cells acquire the ksgA mutations, they produce high-level kasugamycin resistance at an extraordinarily high frequency (100-fold greater frequency than that observed in the ksgA ؉ strain), a phenomenon previously reported for rsmG mutants. This was not the case for other antibiotic resistance mutations (Tsp r and Rif r ), indicating that the high frequency of emergence of a mutation for high-level kasugamycin resistance in the genetic background of ksgA is not due simply to increased persistence of the ksgA strain. Comparative genome sequencing showed that a mutation in the speD gene encoding S-adenosylmethionine decarboxylase is responsible for the observed high-level kasugamycin resistance. ksgA speD double mutants showed a markedly reduced level of intracellular spermidine, underlying the mechanism of high-level resistance. A growth competition assay indicated that, unlike rsmG mutation, the ksgA mutation is disadvantageous for overall growth fitness. This study clarified the similarities and differences between ksgA mutation and rsmG mutation, both of which share a common characteristic-failure to methylate the bases of 16S rRNA. Coexistence of the ksgA mutation and the rsmG mutation allowed cell viability. We propose that the ksgA mutation, together with the rsmG mutation, may provide a novel clue to uncover a still-unknown mechanism of mutation and ribosomal function.

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“…16,17 In addition, kanamycin and capreomycin resistance were conferred by eis and tlyA gene mutations, respectively. 18,19 Saudi Arabia is the third biggest Arab country in the world with a moderate annual TB burden (22 cases/100,000 populations). 2 A moderate level of MDR-TB prevalence (4%) was recently reported with an increasing level of overall resistance (23.6%) to first-line drugs.…”

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confidence: 99%

First Insight Into the Fluoroquinolone and Aminoglycoside Resistance of Multidrug-Resistant Mycobacterium tuberculosis in Saudi Arabia

Varghese

Al‐Hajoj

2017

The American Society of Tropical Medicine and Hygiene

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Abstract. In Saudi Arabia, there were no nationwide screening studies conducted so far to determine the aminoglycoside and fluoroquinolone resistance among multidrug-resistant tuberculosis (MDR-TB) isolates. Therefore, as the first attempt in the country, a retrospective analysis has been conducted on a nationwide collection of 2,956 M. tuberculosis clinical isolates screened with phenotypic drug susceptibility testing to define MDR-TB. Enrolled MDR-TB isolates were subjected to second-line drug susceptibility testing, detection of mutations conferring resistance to aminoglycosides and fluoroquinolone, followed by 24-loci mycobacterial interspersed repetitive unitvariable number of tandem repeat typing and spoligotyping. Overall, 83 isolates were identified as MDR-TB, and 13 (15.7%) isolates showed resistance to second-line drugs. Moxifloxacin (low level) showed higher resistant rates (10.8%) followed by ofloxacin (7.2%), capreomycin (3.6%), kanamycin (3.6%), and amikacin (2.4%). Overall fluoroquinolone resistance was 12%, whereas aminoglycoside resistance was 7.2%. Predominant mutations conferring resistance to fluoroquinolone were found in gyrA A90V and D94G, whereas aminoglycoside resistance was observed only with rrs gene A1401G mutation. The corresponding strain lineages predominated with Indo-Oceanic and EastAfrican Indian origin. Interestingly, none of the isolates with second-line drug resistance was defined as extensively drug-resistant TB (XDR-TB). Surprisingly, many isolates (50.6%) were panresistant to first-line drugs. Saudi Arabia faces considerable burden of fluoroquinolone-and aminoglycoside-resistant MDR-TB. Higher incidence of panresistant MDR-TB reveals a threat for the emergence of XDR-TB strains in the near future.

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Mutation of tlyA Confers Capreomycin Resistance in Mycobacterium tuberculosis

Cited by 202 publications

References 42 publications

Polymorphisms Associated with Resistance and Cross-Resistance to Aminoglycosides and Capreomycin in Mycobacterium tuberculosis Isolates from South Korean Patients with Drug-Resistant Tuberculosis

Polymorphisms Associated with Resistance and Cross-Resistance to Aminoglycosides and Capreomycin in Mycobacterium tuberculosis Isolates from South Korean Patients with Drug-Resistant Tuberculosis

Inactivation of KsgA, a 16S rRNA Methyltransferase, Causes Vigorous Emergence of Mutants with High-Level Kasugamycin Resistance

First Insight Into the Fluoroquinolone and Aminoglycoside Resistance of Multidrug-Resistant Mycobacterium tuberculosis in Saudi Arabia

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