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Tetracycline resistance determinants in Mycobacterium and Streptomyces species.

ABSTRACT: Two of seven tetracycline-resistant (Tcr) Mycobacterium fortuitum group isolates and six Tcr clinical Streptomyces isolates carried gram-positive Tcr determinants (Tet K and Tet L) and Streptomyces resistance determinants (Otr A, Otr B, and Otr C). This represents the first documentation of the acquisition by mycobacteria of determinants coding for antibiotic resistance and suggests the potential for the spread of antibiotic resistance determinants within mycobacterial species.

SUBMITTER: Pang Y

PROVIDER: S-EPMC188220 | biostudies-other | 1994 Jun

REPOSITORIES: biostudies-other

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Tetracycline resistance determinants in Mycobacterium and Streptomyces species.

Pang Y Y Brown B A BA Steingrube V A VA Wallace R J RJ Roberts M C MC

Antimicrobial agents and chemotherapy 19940601 6

Two of seven tetracycline-resistant (Tcr) Mycobacterium fortuitum group isolates and six Tcr clinical Streptomyces isolates carried gram-positive Tcr determinants (Tet K and Tet L) and Streptomyces resistance determinants (Otr A, Otr B, and Otr C). This represents the first documentation of the acquisition by mycobacteria of determinants coding for antibiotic resistance and suggests the potential for the spread of antibiotic resistance determinants within mycobacterial species. ...[more]

PMID: 8092846

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Project description:Tetracyclines have been one of the most successful classes of antibiotics. However, its extensive use has led to the emergence of widespread drug resistance, resulting in discontinuation of use against several bacterial infections. Prominent resistance mechanisms include drug efflux and the use of ribosome protection proteins. Infrequently, tetracyclines can be inactivated by the TetX class of enzymes, also referred to as tetracycline destructases. Low levels of tolerance to tetracycline in Mycobacterium smegmatis and Mycobacterium tuberculosis have been previously attributed to the WhiB7-dependent TetV/Tap efflux pump. However, Mycobacterium abscessus is ?500-fold more resistant to tetracycline than M. smegmatis and M. tuberculosis In this report, we show that this high level of resistance to tetracycline and doxycycline in M. abscessus is conferred by a WhiB7-independent tetracycline-inactivating monooxygenase, MabTetX (MAB_1496c). The presence of sublethal doses of tetracycline and doxycycline results in a >200-fold induction of MabTetX, and an isogenic deletion strain is highly sensitive to both antibiotics. Further, purified MabTetX can rapidly monooxygenate both antibiotics. We also demonstrate that expression of MabTetX is repressed by MabTetRx, by binding to an inverted repeat sequence upstream of MabTetRx; the presence of either antibiotic relieves this repression. Moreover, anhydrotetracycline (ATc) can effectively inhibit MabTetX activity in vitro and decreases the MICs of both tetracycline and doxycycline in vivo Finally, we show that tigecycline, a glycylcycline tetracycline, not only is a poor substrate of MabTetX but also is incapable of inducing the expression of MabTetX. This is therefore the first demonstration of a tetracycline-inactivating enzyme in mycobacteria. It (i) elucidates the mechanism of tetracycline resistance in M. abscessus, (ii) demonstrates the use of an inhibitor that can potentially reclaim the use of tetracycline and doxycycline, and (iii) identifies two sequential bottlenecks-MabTetX and MabTetRx-for acquiring resistance to tigecycline, thereby reiterating its use against M. abscessus.

Project description:Pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid by the enzyme pyrazinamidase, encoded by the pncA gene in Mycobacterium tuberculosis. Molecular identification of mutations in pncA offers the potential for rapid detection of pyrazinamide resistance (PZA(r)). However, the genetic variants are highly variable and scattered over the full length of pncA, complicating the development of a molecular test. We performed a large multicenter study assessing pncA sequence variations in 1,950 clinical isolates, including 1,142 multidrug-resistant (MDR) strains and 483 fully susceptible strains. The results of pncA sequencing were correlated with phenotype, enzymatic activity, and structural and phylogenetic data. We identified 280 genetic variants which were divided into four classes: (i) very high confidence resistance mutations that were found only in PZA(r) strains (85%), (ii) high-confidence resistance mutations found in more than 70% of PZA(r) strains, (iii) mutations with an unclear role found in less than 70% of PZA(r) strains, and (iv) mutations not associated with phenotypic resistance (10%). Any future molecular diagnostic assay should be able to target and identify at least the very high and high-confidence genetic variant markers of PZA(r); the diagnostic accuracy of such an assay would be in the range of 89.5 to 98.8%. Importance: Conventional phenotypic testing for pyrazinamide resistance in Mycobacterium tuberculosis is technically challenging and often unreliable. The development of a molecular assay for detecting pyrazinamide resistance would be a breakthrough, directly overcoming both the limitations of conventional testing and its related biosafety issues. Although the main mechanism of pyrazinamide resistance involves mutations inactivating the pncA enzyme, the highly diverse genetic variants scattered over the full length of the pncA gene and the lack of a reliable phenotypic gold standard hamper the development of molecular diagnostic assays. By analyzing a large number of strains collected worldwide, we have classified the different genetic variants based on their predictive value for resistance which should lead to more rapid diagnostic tests. This would assist clinicians in improving treatment regimens for patients.

Dataset Information

Tetracycline resistance determinants in Mycobacterium and Streptomyces species.

Publications

Tetracycline resistance determinants in Mycobacterium and Streptomyces species.

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