New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria

Pietro Picconi, Charlotte K. Hind, Kazi S. Nahar, Shirin Jamshidi, Lucia Di Maggio, Naima Saeed, Bonnie Evans, Jessica Solomons, Matthew Wand, J. Mark Sutton, Khondaker Miraz Rahman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

It is urgent to find new antibiotic classes with activity against multidrug-resistant (MDR) Gram-negative pathogens as the pipeline of antibiotics is essentially empty. Modified pyrrolobenzodiazepines with a C8-linked aliphatic heterocycle provide a new class of broad-spectrum antibacterial agents with activity against MDR Gram-negative bacteria, including WHO priority pathogens. The structure-activity relationship established that the third ring was particularly important for Gram-negative activity. Minimum inhibitory concentrations for the lead compounds ranged from 0.125 to 2 mg/L for MDR Gram-negative, excluding Pseudomonas aeruginosa, and between 0.03 and 1 mg/L for MDR Gram-positive species. The lead compounds were rapidly bactericidal with >5 log reduction in viable count within 4 h for Acinetobacter baumannii and Klebsiella pneumoniae. The lead compound inhibited DNA gyrase in gel-based assays, with an IC50 of 3.16 ± 1.36 mg/L. This study provides a new chemical scaffold for developing novel broad-spectrum antibiotics which can help replenish the pipeline of antibiotics.

Original languageEnglish
Pages (from-to)6941-6958
Number of pages18
JournalJournal of Medicinal Chemistry
Volume63
Issue number13
DOIs
Publication statusPublished - 9 Jul 2020

Bibliographical note

Funding Information:
Funding was received from PHE Pipeline (project 109502), Grant-in Aid project (Project 109506) and a Medical Research Council Confidence in Concept grant (award code MC_PC_13065). P.P. was funded by a King’s Health School Studentship. Strains were kindly supplied by Dr Katie Hopkins and Dr Daniele Meunier, at PHE AMR and HCAI Reference Unit. P. aeruginosa and K. pneumoniae transposon mutants were provided by the Manoil Laboratory, University of Washington, supported by grant # NIH P30 DK089507.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Fingerprint

Dive into the research topics of 'New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria'. Together they form a unique fingerprint.

Cite this