Induced tigecycline resistance in<i>Streptococcus pneumoniae</i>mutants reveals mutations in ribosomal proteins and rRNA

Lupien, Andréanne; Gingras, Hélène; Leprohon, Philippe; Ouellette, Marc

doi:10.1093/jac/dkv211

Cited by 38 publications

(26 citation statements)

References 68 publications

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“…Mutations affecting TET binding sites of the 30S ribosomal subunit have been shown to confer TET and TGC resistance in several bacterial species (15)(16)(17). The mutational characteristics of OMCinduced resistance in E. faecalis in this study were consistent with the prior identification of various target-interaction related mutations in individual copies of 16S rRNA in bacteria with TGC-induced resistance (16). We detected mutations in all four 16S rRNA gene copies in E. faecalis under OMC pressure.…”

Section: Discussionsupporting

confidence: 89%

“…However, competition studies with radiolabeled TET indicate that OMC can inhibit in vitro translation at half the concentration required for TET (17), suggesting that OMC may have a 2-fold stronger affinity than TET for the ribosome. Mutations affecting TET binding sites of the 30S ribosomal subunit have been shown to confer TET and TGC resistance in several bacterial species (15)(16)(17). The mutational characteristics of OMCinduced resistance in E. faecalis in this study were consistent with the prior identification of various target-interaction related mutations in individual copies of 16S rRNA in bacteria with TGC-induced resistance (16).…”

Section: Discussionsupporting

confidence: 86%

“…These drugs are regarded as last-resort antimicrobial treatments for infections by difficult-to-treat bacteria, such as multidrug-resistant E. faecalis. TGC resistance has been linked to genetic mutations that affect the 30S ribosomal subunit of TET binding sites-including mutations that affect the genes encoding 16SrRNA (four copies) and ribosomal protein S10 -as well as the overexpression of genes that encode efflux pump regulators, such as soxS, marA, ramA, and robA (15)(16)(17)(18). Moreover, overexpression of tet(M) and tet(K) has been shown to increase TGC MIC values and favor the evolution of resistance in Enterococcus faecium (19).…”

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confidence: 99%

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Omadacycline Efficacy against Enterococcus faecalis Isolated in China: In Vitro Activity, Heteroresistance, and Resistance Mechanisms

Wang

et al. 2020

Antimicrob Agents Chemother

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This study aimed to evaluate the in vitro antimicrobial activity, heteroresistance emergence, and resistance mechanism of omadacycline (OMC) in clinical Enterococcus faecalis isolates from China. A total of 276 isolates were collected retrospectively in China from 2011 to 2015. The MICs of OMC, doxycycline (DOX), and minocycline (MIN) against E. faecalis were determined by broth microdilution. Tetracycline (TET)-specific resistance genes and multilocus sequence typing (MLST) of the isolates were investigated using PCR. The detection frequency of OMC heteroresistance in E. faecalis was evaluated with population analysis profiling (PAP). The mechanism of OMC heteroresistance and resistance in E. faecalis was examined by amplifying 30S ribosomal subunit genes, RNA sequencing (RNA-Seq), and in vitro recombination experiments. The OMC MICs of clinical E. faecalis isolates ranged from ≤0.06 to 1.0 mg/liter, and 42% of the E. faecalis isolates with an OMC MIC of 1.0 mg/liter were found to be sequence type 16 (ST16). Six OMC-heteroresistant isolates with MIC values of ≤0.5 mg/liter were detected among 238 E. faecalis isolates. The resistant subpopulations of heteroresistant isolates showed OMC MICs in the range of 2 to 4 mg/liter and were found without 30S ribosomal subunit gene mutations. Moreover, RNA sequencing and in vitro recombination experiments demonstrated that overexpression of a bone morphogenetic protein (BMP) family ATP-binding cassette (ABC) transporter substrate-binding protein, OG1RF_RS00630, facilitated OMC heteroresistance in E. faecalis. In conclusion, OMC exhibited better activity against clinical E. faecalis isolates from China than that of DOX or MIN, and overexpression of OG1RF_RS00630 in E. faecalis facilitated the development of OMC heteroresistance.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 86%

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confidence: 99%

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Omadacycline Efficacy against Enterococcus faecalis Isolated in China: In Vitro Activity, Heteroresistance, and Resistance Mechanisms

Wang

et al. 2020

Antimicrob Agents Chemother

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“…Tigecycline is the first of this new generation of tetracyclines to enter clinical use, being effective against MDR pathogens including carbapenem and colistin resistant microorganisms and those expressing specific tetracycline eﬄux systems and RPPs (Fluit et al, 2005; Cai et al, 2011). However, it is worrisome that resistance to tigecycline has already been described and associated with multidrug eﬄux systems and ribosomal mutations (Villa et al, 2014; Zhong et al, 2014; Lupien et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Eﬄux in the Oral Metagenome: The Discovery of a Novel Tetracycline and Tigecycline ABC Transporter

2016

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Antibiotic resistance in human bacterial pathogens and commensals is threatening our ability to treat infections and conduct common medical procedures. As novel antibiotics are discovered and marketed it is important that we understand how resistance to them may arise and know what environments may act as reservoirs for such resistance genes. In this study a tetracycline and tigecycline resistant clone was identified by screening a human saliva metagenomic library in Escherichia coli EPI300 on agar containing 5 μg/ml tetracycline. Sequencing of the DNA insert present within the tetracycline resistant clone revealed it to contain a 7,765 bp fragment harboring novel ABC half transporter genes, tetAB(60). Mutagenesis studies performed on these genes confirmed that they were responsible for the tetracycline and tigecycline resistance phenotypes. Growth studies performed using E. coli EPI300 clones that harbored either the wild type, the mutated, or none of these genes indicated that there was a fitness cost associated with presence of these genes, with the isolate harboring both genes exhibiting a significantly slower growth than control strains. Given the emergence of E. coli strains that are sensitive only to tigecycline and doxycycline it is concerning that such a resistance mechanism has been identified in the human oral cavity.

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“…It has been reported that overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Enterobacteriaceae (6)(7)(8). Ribosomal protein S10 is also a general target of tigecycline adaptation (9)(10)(11). In addition to the efflux pumps and ribosomal S10 protein described previously, other possible mechanisms of tigecycline resistance require further investigation.…”

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confidence: 88%

Decreased Susceptibility to Tigecycline Mediated by a Mutation in mlaA in Escherichia coli Strains

Wang

et al. 2016

Antimicrob Agents Chemother

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Induced tigecycline resistance inStreptococcus pneumoniaemutants reveals mutations in ribosomal proteins and rRNA

Abstract: This first report about tigecycline resistance mechanisms in S. pneumoniae revealed that, in contrast to Gram-negative species, for which efflux appears central for tigecycline resistance, resistance in the pneumococcus occurs through mutations related to ribosomes.

Cited by 38 publications

References 68 publications

Omadacycline Efficacy against Enterococcus faecalis Isolated in China: In Vitro Activity, Heteroresistance, and Resistance Mechanisms

Omadacycline Efficacy against Enterococcus faecalis Isolated in China: In Vitro Activity, Heteroresistance, and Resistance Mechanisms

Eﬄux in the Oral Metagenome: The Discovery of a Novel Tetracycline and Tigecycline ABC Transporter

Decreased Susceptibility to Tigecycline Mediated by a Mutation in mlaA in Escherichia coli Strains

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