Correlating rrs and eis promoter mutations in clinical isolates of Mycobacterium tuberculosis with phenotypic susceptibility levels to the second-line injectables

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Abstract

The in vitro drug-susceptibility testing of Mycobacterium tuberculosis reports isolates as resistant or susceptible on the basis of single critical concentrations. It is evident that drug resistance in M. tuberculosis is quite heterogeneous, and involves low level, moderate level, and high level of drug-resistant phenotypes. Thus, the aim of our study was to correlate rrs (X52917) and eis (AF144099) promoter mutations, found in M. tuberculosis isolates, with corresponding minimum inhibitory concentrations of amikacin, kanamycin, and capreomycin.

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Laboratory diagnosis of tuberculosis in resource-poor countries: challenges and opportunities.

Evan Lee, Giorgio Roscigno, Jessica Parsons … (2011)

With an estimated 9.4 million new cases globally, tuberculosis (TB) continues to be a major public health concern. Eighty percent of all cases worldwide occur in 22 high-burden, mainly resource-poor settings. This devastating impact of tuberculosis on vulnerable populations is also driven by its deadly synergy with HIV. Therefore, building capacity and enhancing universal access to rapid and accurate laboratory diagnostics are necessary to control TB and HIV-TB coinfections in resource-limited countries. The present review describes several new and established methods as well as the issues and challenges associated with implementing quality tuberculosis laboratory services in such countries. Recently, the WHO has endorsed some of these novel methods, and they have been made available at discounted prices for procurement by the public health sector of high-burden countries. In addition, international and national laboratory partners and donors are currently evaluating other new diagnostics that will allow further and more rapid testing in point-of-care settings. While some techniques are simple, others have complex requirements, and therefore, it is important to carefully determine how to link these new tests and incorporate them within a country's national diagnostic algorithm. Finally, the successful implementation of these methods is dependent on key partnerships in the international laboratory community and ensuring that adequate quality assurance programs are inherent in each country's laboratory network.

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Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis.

Thomas Shinnick, G Zaunbrecher, C Sikes … (2009)

The emergence of multidrug-resistant (MDR) tuberculosis (TB) highlights the urgent need to understand the mechanisms of resistance to the drugs used to treat this disease. The aminoglycosides kanamycin and amikacin are important bactericidal drugs used to treat MDR TB, and resistance to one or both of these drugs is a defining characteristic of extensively drug-resistant TB. We identified mutations in the -10 and -35 promoter region of the eis gene, which encodes a previously uncharacterized aminoglycoside acetyltransferase. These mutations led to a 20-180-fold increase in the amount of eis leaderless mRNA transcript, with a corresponding increase in protein expression. Importantly, these promoter mutations conferred resistance to kanamycin [5 microg/mL < minimum inhibitory concentration (MIC)

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Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis.

Thomas Shinnick, Courtney Maus, B Plikaytis (2005)

Capreomycin, kanamycin, amikacin, and viomycin are drugs that are used to treat multidrug-resistant tuberculosis. Each inhibits translation, and cross-resistance to them is a concern during therapy. A recent study revealed that mutation of the tlyA gene, encoding a putative rRNA methyltransferase, confers capreomycin and viomycin resistance in Mycobacterium tuberculosis bacteria. Mutations in the 16S rRNA gene (rrs) have been associated with resistance to each of the drugs; however, reports of cross-resistance to the drugs have been variable. We investigated the role of rrs mutations in capreomycin resistance and examined the molecular basis of cross-resistance to the four drugs in M. tuberculosis laboratory-generated mutants and clinical isolates. Spontaneous mutants were generated to the drugs singularly and in combination by plating on medium containing one or two drugs. The frequencies of recovery of the mutants on single- and dual-drug plates were consistent with single-step mutations. The rrs genes of all mutants were sequenced, and the tlyA genes were sequenced for mutants selected on capreomycin, viomycin, or both; MICs of all four drugs were determined. Three rrs mutations (A1401G, C1402T, and G1484T) were found, and each was associated with a particular cross-resistance pattern. Similar mutations and cross-resistance patterns were found in drug-resistant clinical isolates. Overall, the data implicate rrs mutations as a molecular basis for resistance to each of the four drugs. Furthermore, the genotypic and phenotypic differences seen in the development of cross-resistance when M. tuberculosis bacteria were exposed to one or two drugs have implications for selection of treatment regimens.