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

doi:10.1021/acs.jmedchem.0c00328

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 journal › Article › peer-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 language	English
Pages (from-to)	6941-6958
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	13
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00328
Publication status	Published - 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.

Access to Document

10.1021/acs.jmedchem.0c00328

Cite this

Picconi, P., Hind, C. K., Nahar, K. S., Jamshidi, S., Di Maggio, L., Saeed, N., Evans, B., Solomons, J., Wand, M., Sutton, J. M., & Rahman, K. M. (2020). New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria. Journal of Medicinal Chemistry, 63(13), 6941-6958. https://doi.org/10.1021/acs.jmedchem.0c00328

@article{cb728d17094c430f989d57535e0034e6,

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

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. ",

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

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{\textquoteright}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 {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = jul,

day = "9",

doi = "10.1021/acs.jmedchem.0c00328",

language = "English",

volume = "63",

pages = "6941--6958",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "13",

}

Picconi, P, Hind, CK, Nahar, KS, Jamshidi, S, Di Maggio, L, Saeed, N, Evans, B, Solomons, J, Wand, M , Sutton, JM & Rahman, KM 2020, 'New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria', Journal of Medicinal Chemistry, vol. 63, no. 13, pp. 6941-6958. https://doi.org/10.1021/acs.jmedchem.0c00328

TY - JOUR

T1 - New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria

AU - Picconi, Pietro

AU - Hind, Charlotte K.

AU - Nahar, Kazi S.

AU - Jamshidi, Shirin

AU - Di Maggio, Lucia

AU - Saeed, Naima

AU - Evans, Bonnie

AU - Solomons, Jessica

AU - Wand, Matthew

AU - Sutton, J. Mark

AU - Rahman, Khondaker Miraz

N1 - 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.

PY - 2020/7/9

Y1 - 2020/7/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85088210698&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.0c00328

DO - 10.1021/acs.jmedchem.0c00328

M3 - Article

C2 - 32515951

AN - SCOPUS:85088210698

VL - 63

SP - 6941

EP - 6958

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this