Activity of rx-04 pyrrolocytosine protein synthesis inhibitors against multidrug-resistant gram-negative bacteria

Anna Vickers, Shazad Mushtaq, Neil Woodford, Michel Doumith, David Livermore*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Pyrrolocytosines RX-04A to -D are designed to bind to the bacterial 50S ribosomal subunit differently from currently used antibiotics. The four analogs had broad anti-Gram-negative activity: RX-04A—the most active analog—inhibited 94.7% of clinical Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa at 0.5 to 4 g/ml, with no MICs of 8 g/ml. MICs for multidrug-resistant (MDR) carbapenemase producers were up to 2-fold higher than those for control strains; values were highest for one Serratia isolate with porin and efflux lesions. mcr-1 did not affect MICs.

Original languageEnglish
Article numbere00689-18
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number8
DOIs
Publication statusPublished - Aug 2018

Bibliographical note

Funding Information:
This study was funded by Melinta Therapeutics, Inc. D.M.L. is on advisory boards of or does ad hoc consultancy for Accelerate, Achaogen, Adenium, Allecra, AstraZeneca, Auspherix, Basilea, BioVersys, Centauri, Discuva, Integra-Holdings, Meiji, Melinta, Nordic, Pfizer, Roche, Shionogi, Taxis, T.A.Z., Tetraphase, The Medicines Company, VenatoRx, Wockhardt, Zambon, and Zealand. D.M.L. has done paid lectures for Astellas, AstraZeneca, bioMerieux, Beckman Coulter, Cardiome, Cepheid, Merck, Pfizer, and Nordic. Relevant shareholdings include Dechra, GSK, Merck, Perkin Elmer, and Pfizer, amounting to 10% of portfolio value. The other authors have no personal items to declare; however, PHE’s AMRHAI Reference Unit has received financial support for conference attendance, lectures, research projects or contracted evaluations from numerous sources, including Accelerate Diagnostics, Achaogen, Inc., Allecra Therapeutics, Amplex, AstraZeneca UK, Ltd., AusDiagnostics, Basilea Pharma-ceutica, Becton Dickinson Diagnostics, bioMérieux, Bio-Rad Laboratories, the BSAC, Cepheid, Check-Points B.V., Cubist Pharmaceuticals, Department of Health, Enigma Diagnostics, the European Centre for Disease Prevention and Control, Food Standards Agency, GlaxoSmithKline Services, Ltd., Helperby Therapeutics, Henry Stewart Talks, IHMA, Ltd., Innovate UK, Kalidex Pharmaceuticals, Melinta Therapeutics, Merck Sharpe & Dohme Corp., Meiji Seika Pharma Co., Ltd., Mobidiag, Momentum Biosciences, Ltd., Neem Biotech, NIHR, Nordic Pharma, Ltd., Norgine Pharmaceuticals, Rempex Pharmaceuticals, Ltd., Roche, Rokitan, Ltd., Smith & Nephew UK, Ltd., Shionogi & Co., Ltd., Trius Therapeutics, VenatoRx Pharmaceuticals, Wockhardt, Ltd., and the World Health Organization.

Funding Information:
This study was funded by Melinta Therapeutics, Inc.

Publisher Copyright:
© Crown copyright 2018

Keywords

  • 50S ribosomal subunit
  • Blasticidin
  • Mcr-1
  • Pyrrolocytosine

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