Tet38 Efflux Pump Contributes to Fosfomycin Resistance in Staphylococcus aureus

Truong-Bolduc, Que Chi; Wang, Y.; Hooper, David C.

doi:10.1128/aac.00927-18

Cited by 19 publications

(13 citation statements)

References 16 publications

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“…Recent studies have shown that the tet38 gene exerts a specific effect on fosfomycin resistance. According to the study by Truong-Bolduc, the overexpression of tet38 resulted in a fourfold increase in the MIC of fosfomycin compared with that of the parent strain ( Truong-Bolduc et al, 2018 ). The results of the current study showed that the expression of the tet38 efflux pump gene in fosfomycin-resistant strains JP3212, JP3535, JP3592, and JP3600 was significantly higher than that in the control strain ATCC29213 and the susceptible strains ( P = 0.007, P = 0.002, P < 0.001, P < 0.001, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the MurA target enzyme and transporters (GlpT and UhpT) have been shown to be responsible for fosfomycin resistance ( Michalopoulos et al, 2011 ). Additionally, the overexpression of target enzymes, MurA and Tet38 efflux pump, also contributes to fosfomycin resistance in S. aureus ( Truong-Bolduc et al, 2018 ). Notably, there are no reports yet suggesting that fosfomycin can stimulate the expression of the efflux pump gene and mediate drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms and Epidemiology of Fosfomycin Resistance in Staphylococcus aureus Isolated From Patients at a Teaching Hospital in China

Chen

Zeng

et al. 2020

Front. Microbiol.

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Staphylococcus aureus is a major cause of hospital- and community-acquired infections placing a significant burden on the healthcare system. With the widespread of multidrug-resistant bacteria and the lack of effective antibacterial drugs, fosfomycin has gradually attracted attention as an “old drug.” Thus, investigating the resistance mechanisms and epidemiology of fosfomycin-resistant S. aureus is an urgent requirement. In order to investigate the mechanisms of resistance, 11 fosfomycin-resistant S. aureus isolates were analyzed by PCR and sequencing. The genes, including fosA , fosB , fosC , fosD , fosX , and tet38 , as well as mutations in murA , glpT , and uhpT were identified. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate the expression of the target enzyme gene murA and the efflux pump gene tet38 under the selection pressure of fosfomycin. Furthermore, multilocus sequence typing (MLST) identified a novel sequence type (ST 5708) of S. aureus strains. However, none of the resistant strains carried fosA , fosB , fosC , fosD , and fosX genes in the current study, and 12 distinct mutations were detected in the uhpT (3), glpT (4), and murA (5) genes. qRT-PCR revealed an elevated expression of the tet38 gene when exposed to increasing concentration of fosfomycin among 8 fosfomycin-resistant S. aureus strains and reference strain ATCC 29213. MLST analysis categorized the 11 strains into 9 STs. Thus, the mutations in the uhpT , glpT , and murA genes might be the primary mechanisms underlying fosfomycin resistance, and the overexpression of efflux pump gene tet38 may play a major role in the fosfomycin resistance in these isolates.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms and Epidemiology of Fosfomycin Resistance in Staphylococcus aureus Isolated From Patients at a Teaching Hospital in China

Chen

Zeng

et al. 2020

Front. Microbiol.

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“…Tet38 functions as a broad-spectrum membrane transporter in S. aureus, and its substrate spectrum includes chemically unrelated compounds (palmitoleic acid and glycerol-3-phosphate) and antibiotics (tetracycline and fosfomycin). Tet38 also contributes to S. aureus invasion of A549 epithelial cells (14,20,21,23), but there is limited understanding of the mechanism by which it facilitates bacterial internalization into host cells. Using antibodies against host cell receptors CD36 and TLR-2 to block the entrance of S. aureus, we found that a blockage with anti-CD36 antibody was effective only in the presence of Tet38, and anti-TLR-2 antibody had an additional 2-fold effect on internalization of the tet38 mutant QT7.…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that the Tet38 efflux pump, which extrudes diverse substrates such as tetracycline, fosfomycin, free fatty acids, and glycerol-3-phosphate, is involved in the internalization of S. aureus by A549 epithelial cells, as evidenced by a 5-fold reduction in the recovery of a tet38 mutant after A549 cell invasion (13,14). Treatment of A549 cells with anti-CD36 antibody reduced binding of wild-type cells 2-fold but had no effect on the tet38 mutant, suggesting that Tet38 interacted with CD36 in host cell invasion (13).…”

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confidence: 99%

Tet38 of Staphylococcus aureus Binds to Host Cell Receptor Complex CD36–Toll-Like Receptor 2 and Protects from Teichoic Acid Synthesis Inhibitors Tunicamycin and Congo Red

2019

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Using an affinity column retention assay, we showed that the purified Tet38 membrane transporter of Staphylococcus aureus bound specifically to host cell CD36 and to the complex CD36–Toll-like receptor 2 (TLR-2), but not to TLR-2 alone or TLR-2 and S. aureus lipoteichoic acid (LTA). We tested the effect of LTA on the internalization of S. aureus tet38 mutant QT7 versus RN6390 by A549 epithelial cells. Addition of anti-LTA antibody to the bacteria prior to adding to A549 cells reduced internalization of QT7 2-fold compared to that with nonspecific antibody treatment. QT7 internalized 4- to 6-fold less than RN6390 with or without anti-LTA antibody. These data suggested that Tet38 and LTA were independently involved in the invasion process. The wall teichoic acid (WTA) inhibitor tunicamycin had an 8-fold decrease in activity with overexpression of tet38 and a 2-fold increase in activity in QT7 (tet38). Reserpine (an inhibitor of efflux pumps) reduced the effect of tet38 overexpression on tunicamycin resistance 4-fold. In addition, tet38 affected growth in the presence of LTA inhibitor Congo red, with overexpression increasing growth and deletion of tet38 reducing growth. In conclusion, Tet38 contributes to S. aureus invasion of A549 via direct binding to CD36 of the complex CD36–TLR-2, and LTA independently bound to TLR-2. The reduction of tunicamycin resistance in the presence of reserpine and the survival ability of the tet38 overexpressor in the presence of Congo red suggest that Tet38 can also protect the synthesis of LTA and WTA in S. aureus against their inhibitors, possibly functioning as an efflux pump.

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“…Ponieważ spektrum substratowe systemów Mex obejmuje wiele różnych klas substancji przeciwbakteryjnych, ich podwyższona synteza może przyczyniać się do występowania wielooporności u Pseudomonas. Fosfomycyna nie stanowi substratu dla systemów typu Mex, natomiast dowiedziono, że może być usuwana z komórek bakteryjnych przy udziale pompy Tet38 [60,94].…”

Section: Czynne Usuwanie Cząsteczek Substancji Przeciwbakteryjnejunclassified

Antibiotics And Bacteria: Mechanisms Of Action And Resistance Strategies

Skarżyńska

Zając

Wasyl

2020

Postępy Mikrobiologii - Advancements of Microbiology

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Wpłynęło w sierpniu, zaakceptowano w grudniu 2019 r. Streszczenie: Oporność bakterii na substancje przeciwbakteryjne jest jednym z najistotniejszych problemów epidemiologicznych notowanych w skali globalnej. Powszechne stosowanie w medycynie i weterynarii substancji przeciwbakteryjnych należących do tych samych klas, niejednokrotnie bez potwierdzenia w laboratorium skuteczności zastosowanej substancji czynnej, przyczynia się do selekcji opornych bakterii u ludzi i zwierząt oraz ich rozprzestrzenienia w przyrodzie. Narastająca antybiotykooporność bakterii patogennych prowadzi do poważnych konsekwencji zarówno dla zdrowia ludzi jak i zwierząt. Równie ważna jest oporność bakterii komensalnych, gdyż stanowią one rezerwuar i wektor genów oporności w środowisku. Ekspozycja na środki przeciwbakteryjne należące do różnych klas może prowadzić do oporności krzyżowej i selekcji genów rozprzestrzeniających się horyzontalnie z udziałem ruchomych elementów genetycznych. Alarmujący jest fakt pojawienia się przenoszonej z udziałem plazmidów oporności na substancje o najwyższym poziomie istotności dla medycyny ludzkiej np. karbapenemy czy polimyksyny. Na przykładzie antybiotyków zaliczanych do kategorii "krytycznie istotnych" możliwe jest omówienie niemal wszystkich sposobów działania substancji przeciwbakteryjnych oraz bakteryjnych mechanizmów antybiotykooporności. Do efektywnej walki z rosnącą antybiotykoopornością bakterii niezbędna jest znajomość mechanizmów oporności oraz sposobów ich nabywania przez bakterie. Celem artykułu jest przegląd sposobów w jaki substancje krytycznie istotne z punktu widzenia ochrony zdrowia publicznego działają na komórki bakteryjne oraz przedstawienie złożonych mechanizmów, które odpowiadają za oporność na te substancje oraz genów warunkujących pojawienie się oporności.

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Tet38 Efflux Pump Contributes to Fosfomycin Resistance in Staphylococcus aureus

Cited by 19 publications

References 16 publications

Molecular Mechanisms and Epidemiology of Fosfomycin Resistance in Staphylococcus aureus Isolated From Patients at a Teaching Hospital in China

Molecular Mechanisms and Epidemiology of Fosfomycin Resistance in Staphylococcus aureus Isolated From Patients at a Teaching Hospital in China

Tet38 of Staphylococcus aureus Binds to Host Cell Receptor Complex CD36–Toll-Like Receptor 2 and Protects from Teichoic Acid Synthesis Inhibitors Tunicamycin and Congo Red

Antibiotics And Bacteria: Mechanisms Of Action And Resistance Strategies

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