Noncytotoxic Pyrrolobenzodiazepine-Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

Pietro Picconi; Rose Jeeves; Christopher William Moon; Shirin Jamshidi; Kazi S. Nahar; Mark Laws; Joanna Bacon; Khondaker Miraz Rahman

doi:10.1021/acsomega.9b00834

Noncytotoxic Pyrrolobenzodiazepine-Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

Pietro Picconi, Rose Jeeves, Christopher William Moon, Shirin Jamshidi, Kazi S. Nahar, Mark Laws, Joanna Bacon^*, Khondaker Miraz Rahman

^*Corresponding author for this work

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Abstract

The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.

Original language	English
Pages (from-to)	20873-20881
Number of pages	9
Journal	ACS Omega
Volume	4
Issue number	25
DOIs	https://doi.org/10.1021/acsomega.9b00834
Publication status	Published - 17 Dec 2019

Bibliographical note

Funding Information:
The authors thank King’s College London Health School for a Ph.D. studentship to P.P. (award no. JGA3804), Medical Research Council (award no. MC_PC_13065), and Public Health England and Department of Health for supporting this work. We acknowledge the PHE National Mycobacterium Reference Laboratory (NMRL) for providing M. tuberculosis Beijing strains 1192/015 and 08/00483E. The views expressed in this publication are those of the authors and not necessarily those of Public Health England or the Department of Health.

Publisher Copyright:
Copyright © 2019 American Chemical Society.

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title = "Noncytotoxic Pyrrolobenzodiazepine-Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis",

abstract = "The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.",

author = "Pietro Picconi and Rose Jeeves and Moon, {Christopher William} and Shirin Jamshidi and Nahar, {Kazi S.} and Mark Laws and Joanna Bacon and Rahman, {Khondaker Miraz}",

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AU - Bacon, Joanna

AU - Rahman, Khondaker Miraz

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N2 - The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.

AB - The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.

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ER -

Noncytotoxic Pyrrolobenzodiazepine-Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

Abstract

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