Intrinsic resistance of Escherichia coli to mureidomycin A and C due to expression of the multidrug efflux system AcrAB-TolC: comparison with the efflux systems of mureidomycin-susceptible Pseudomonas aeruginosa

Gotoh, Naomasa; Murata, Takeshi; Ozaki, T.; Kimura, Tadashi; Kondo, Akiko; Nishino, Takeshi

doi:10.1007/s10156-002-0205-2

Cited by 13 publications

(6 citation statements)

References 18 publications

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“…The obtained sansanmycin analogues MX-1–10 were tested for their antibacterial activity against different bacteria including gram-negative bacteria, gram-positive bacteria as well as M. tuberculosis H 37 Rv and clinically isolated MDR and XDR M. tuberculosis strains (Table 2 ). As expected, all the tested compounds (except MX-3) displayed different degrees of activity against E. coli ΔtolC mutant strain, which was consistent with previous results that UPAs can be exported by the AcrAB-TolC efflux system in E. coli [ 29 ]. Among them, sansanmycin MX-2 and MX-6 remained potency against P. aeruginosa equivalent to sansanmycin A. Interestingly, compound MX-6 exhibited antibacterial activity against gram-positive B. subtilis , which was not found in natural UPAs.…”

Section: Resultssupporting

confidence: 91%

Improving the N-terminal diversity of sansanmycin through mutasynthesis

et al. 2016

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BackgroundSansanmycins are uridyl peptide antibiotics (UPAs), which are inhibitors of translocase I (MraY) and block the bacterial cell wall biosynthesis. They have good antibacterial activity against Pseudomonas aeruginosa and Mycobacterium tuberculosis strains. The biosynthetic gene cluster of sansanmycins has been characterized and the main biosynthetic pathway elucidated according to that of pacidamycins which were catalyzed by nonribosomal peptide synthetases (NRPSs). Sananmycin A is the major compound of Streptomyces sp. SS (wild type strain) and it bears a non-proteinogenic amino acid, meta-tyrosine (m-Tyr), at the N-terminus of tetrapeptide chain.ResultsssaX deletion mutant SS/XKO was constructed by the λ-RED mediated PCR targeting method and confirmed by PCR and southern blot. The disruption of ssaX completely abolished the production of sansanmycin A. Complementation in vivo and in vitro could both recover the production of sansanmycin A, and the overexpression of SsaX apparently increased the production of sansanmycin A by 20 %. Six new compounds were identified in the fermentation culture of ssaX deletion mutant. Some more novel sansanmycin analogues were obtained by mutasynthesis, and totally ten sansanmycin analogues, MX-1 to MX-10, were purified and identified by electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR). The bioassay of these sansanmycin analogues showed that sansanmycin MX-1, MX-2, MX-4, MX-6 and MX-7 exhibited comparable potency to sansanmycin A against M. tuberculosis H37Rv, as well as multi-drug-resistant (MDR) and extensive-drug-resistant (XDR) strains. Moreover, sansanmycin MX-2 and MX-4 displayed much better stability than sansanmycin A.ConclusionsWe demonstrated that SsaX is responsible for the biosynthesis of m-Tyr in vivo by gene deletion and complementation. About twenty novel sansanmycin analogues were obtained by mutasynthesis in ssaX deletion mutant SS/XKO and ten of them were purified and structurally identified. Among them, MX-2 and MX-4 showed promising anti-MDR and anti-XDR tuberculosis activity and greater stability than sansanmycin A. These results indicated that ssaX deletion mutant SS/XKO was a suitable host to expand the diversity of the N-terminus of UPAs, with potential to yield more novel compounds with improved activity and/or other properties.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0471-1) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

Improving the N-terminal diversity of sansanmycin through mutasynthesis

et al. 2016

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“…[146] Mureidomycin A and C and simocyclinone D8 (an angucyclinone antibiotic) are also substrates for AcrAB-TolC. [148, 149] YojI, an ABC exporter, functions with TolC and mediates resistance to microcin J25[150] and its expression is modulated by the leucine-responsive regulatory protein (Lrp). [151] Preincubation of FloR pump-producing florfenicol-resistant strains with anti-FloR antibody, in the presence of lysozyme and ethylenediaminotetraacetic acid, increased the intracellular accumulation of florfenicol.…”

Section: Drug Efflux In Gram-negative Bacteriamentioning

confidence: 99%

Efflux-Mediated Drug Resistance in Bacteria

Nikaido²

2009

Drugs

909

875

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Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome although they can also be plasmid-encoded. A previous article (Li X-Z and Nikaido H, Drugs, 2004; 64[2]: 159–204) had provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past five years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

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“…High-level intrinsic pacidamycin resistance in these bacteria could be explained by lack of uptake of the peptide antibiotic, efficient extrusion via efflux pumps, or a combination of these mechanisms. The intrinsic resistance of E. coli to mureidomycins was previously attributed to efflux by the AcrABTolC pump (7,8). A significant limitation for the therapeutic use of pacidamycins with P. aeruginosa is the high frequency (10 Ϫ6 to 10 Ϫ7 ) at which resistant mutants emerge.…”

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confidence: 99%

High-Level Pacidamycin Resistance in Pseudomonas aeruginosa Is Mediated by an Opp Oligopeptide Permease Encoded by the opp-fabI Operon

Mistry¹,

Warren

Cusick

et al. 2013

Antimicrob Agents Chemother

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dPacidamycins (or uridyl peptide antibiotics) possess selective in vivo activity against Pseudomonas aeruginosa. An important limitation for the therapeutic use of pacidamycins with P. aeruginosa is the high frequency (10 ؊6 to 10 ؊7 ) at which resistant mutants emerge. To elucidate the mechanism(s) of this resistance, pacidamycin-resistant P. aeruginosa mutants were isolated. Two types of mutants were obtained. Type 1, or high-level resistance mutants with a pacidamycin MIC of 512 g/ml, were more abundant, with a frequency of ϳ2 ؋ 10 ؊6 , and did not show cross-resistance with other antibiotics. Type 2, low-level resistance mutants, were isolated with a frequency of ϳ10 ؊8 and had a pacidamycin MIC of 64 g/ml (the MIC for the wild-type strain was 4 to 16 g/ml). These mutants were cross-resistant to levofloxacin, tetracycline, and erythromycin and were shown to overexpress either the MexAB-OprM or MexCD-OprJ multidrug resistance efflux pumps. High-level resistant mutants were isolated by transposon mutagenesis and one insertion was localized to oppB, one of two periplasmic binding protein components of an oligopeptide transport system which is encoded by the opp-fabI operon. The Opp system is required for uptake of pacidamycin across the inner membrane, since various opp, but not fabI, mutants were resistant to high levels of pacidamycin. Both of the two putative Opp periplasmic binding proteins, OppA and OppB, were required for pacidamycin uptake. Although both impaired uptake into and efflux from the cell can cause pacidamycin resistance in P. aeruginosa, our data suggest that impaired uptake is the primary reason for the high-frequency and high-level pacidamycin resistance.

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Intrinsic resistance of Escherichia coli to mureidomycin A and C due to expression of the multidrug efflux system AcrAB-TolC: comparison with the efflux systems of mureidomycin-susceptible Pseudomonas aeruginosa

Cited by 13 publications

References 18 publications

Improving the N-terminal diversity of sansanmycin through mutasynthesis

Improving the N-terminal diversity of sansanmycin through mutasynthesis

Efflux-Mediated Drug Resistance in Bacteria

High-Level Pacidamycin Resistance in Pseudomonas aeruginosa Is Mediated by an Opp Oligopeptide Permease Encoded by the opp-fabI Operon

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