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Molecules 2015, 20(5), 7790-7806; doi:10.3390/molecules20057790

Development of a Novel Antimicrobial Screening System Targeting the Pyoverdine-Mediated Iron Acquisition System and Xenobiotic Efflux Pumps

1
Laboratory of Animal Microbiology, Department of Microbial Biotechnology, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori, Amamiya-machi, Aoba-ku, Sendai 981-8555, Japan
2
Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan
3
Department of Biological Science and Technology, Faculty of Engineering, 2-1 Minamijyousanjima-cho, Tokushima 770-8605, Japan
4
Laboratory for Antimicrobial Agents, Kitasato University, 1-15-1 Kitasato, Sagamihara 228-8555, Japan
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Peter J. Rutledge
Received: 9 February 2015 / Revised: 19 March 2015 / Accepted: 23 April 2015 / Published: 29 April 2015
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Abstract

The iron acquisition systems in Pseudomonas aeruginosa are inducible in response to low-iron conditions and important for growth of this organism under iron limitation. OprM is the essential outer membrane subunit of the MexAB-OprM xenobiotic efflux pump. We designed and constructed a new model antimicrobial screening system targeting both the iron-uptake system and xenobiotic efflux pumps. The oprM gene was placed immediately downstream of the ferri-pyoverdine receptor gene, fpvA, in the host lacking chromosomal oprM and the expression of oprM was monitored by an antibiotic susceptibility test under iron depleted and replete conditions. The recombinant cells showed wild-type susceptibility to pump substrate antibiotics, e.g., aztreonam, under iron limitation and became supersusceptible to them under iron repletion, suggesting that expression of oprM is under control of the iron acquisition system. Upon screening of a chemical library comprising 2952 compounds using this strain, a compound—ethyl 2-(1-acetylpiperidine-4-carboxamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate—was found to enhance the efficacy of aztreonam under iron limitation, suggesting that the compound inhibits either the iron acquisition system or the MexAB-OprM efflux pump. This compound was subsequently found to inhibit the growth of wild-type cells in the presence of sublethal amounts of aztreonam, regardless of the presence or absence of dipyridyl, an iron-chelator. The compound was eventually identified to block the function of the MexAB-OprM efflux pump, showing the validity of this new method. View Full-Text
Keywords: antimicrobials; iron acquisition systems; efflux pumps; Pseudomonas aeruginosa antimicrobials; iron acquisition systems; efflux pumps; Pseudomonas aeruginosa
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sato, K.; Ushioda, K.; Akiba, K.; Matsumoto, Y.; Maseda, H.; Ando, T.; Isogai, E.; Nakae, T.; Yoneyama, H. Development of a Novel Antimicrobial Screening System Targeting the Pyoverdine-Mediated Iron Acquisition System and Xenobiotic Efflux Pumps. Molecules 2015, 20, 7790-7806.

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