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

Journal of Medicinal Chemistry
Pietro PicconiKhondaker Miraz Rahman

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.

References

Jul 1, 1988·Molecular Microbiology·M J WalkerJ M Pemberton
Dec 20, 1965·Journal of the American Chemical Society·W LeimgruberJ Berger
Nov 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Michael A JacobsColin Manoil
Aug 29, 2006·Nucleic Acids Research·Anthony MaxwellNatasha O'Hagan
Aug 31, 2006·Antimicrobial Agents and Chemotherapy·Lilian PumbweHannah M Wexler
Jun 15, 2010·Medicinal Research Reviews·Barbara Gerratana
Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
May 2, 2012·The Journal of Antimicrobial Chemotherapy·Khondaker M RahmanPeter W Taylor
Sep 18, 2012·Journal of Bacteriology·Kiara HeldColin Manoil
Nov 11, 2010·ACS Medicinal Chemistry Letters·Khondaker M RahmanDavid E Thurston
Sep 24, 2014·Antimicrobial Agents and Chemotherapy·Jun FanScott D Mills
Nov 20, 2016·Angewandte Chemie·Julia MantajDavid E Thurston
Nov 25, 2016·ACS Medicinal Chemistry Letters·Arnaud C TiberghienPhilip W Howard
Jun 27, 2017·Journal of Medicinal Chemistry·Pietro PicconiKhondaker Miraz Rahman
Feb 16, 2018·Annals of the New York Academy of Sciences·Michelle F Richter, Paul J Hergenrother
May 24, 2018·Nucleic Acids Research·Enis AfganDaniel Blankenberg
Oct 20, 2018·The Lancet Infectious Diseases·Ursula TheuretzbacherStephan Harbarth
Jan 27, 2019·Nature Reviews. Microbiology·Mike Tyers, Gerard D Wright
May 30, 2019·Future Medicinal Chemistry·Anja KolaričNikola Minovski

❮ Previous
Next ❯

Citations

Nov 6, 2020·European Journal of Medicinal Chemistry·Yichao WanZilong Tang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Acinetobacter Infections

Acinetobacter infections have become common in hospitalized patients, especially in the intensive care unit setting and are difficult to treat due to their propensity to develop antimicrobial drug resistance. Discover the latest research on Acinetobacter Infections here.