C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug Resistant Gram-Positive Bacteria.

Paolo Andriollo,Amrit Varsha,Pietro Picconi,Khondaker Miraz Rahman,Kazi S. Nahar,Melanie Clifford,Shirin Jamshidi,Charlotte K. Hind,J. Mark Sutton

doi:10.1021/acsinfecdis.7b00130

Paolo Andriollo, Amrit Varsha + Show 7 more

Open Access

https://doi.org/10.1021/acsinfecdis.7b00130

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Abstract

Antimicrobial resistance has become a major global concern. Development of novel antimicrobial agents for the treatment of infections caused by multidrug resistant (MDR) pathogens is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents initially discovered and isolated from natural sources. Recently, C8-linked PBD biaryl conjugates have been shown to be active against some MDR Gram-positive strains. To explore the role of building block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied. The compounds showed minimum inhibitory concentrations (MICs) in the range of 0.125-32 μg/mL against MDR Gram-positive strains with a bactericidal mode of action. The results showed that a single inversion of amide bonds reduces the activity while the double inversion restores the activity against MDR pathogens. All inverted compounds did not stabilize DNA and lacked eukaryotic toxicity. The compounds inhibit DNA gyrase in vitro, and the most potent compound was equally active against both wild-type and mutant DNA gyrase in a biochemical assay. The observed activity of the compounds against methicillin resistant S.aureus (MRSA) strains with equivalent gyrase mutations is consistent with gyrase inhibition being the mechanism of action in vivo, although this has not been definitively confirmed in whole cells. This conclusion is supported by a molecular modeling study showing interaction of the compounds with wild-type and mutant gyrases. This study provides important SAR information about this new class of antibacterial agents.

Highlights

The resistance of pathogens to antibacterial agents has become a major global concern
Of great concern among all the bacteria that are developing resistance is a group of pathogens termed the ESKAPE pathogens,3 which are characterized by the rapid acquisition of resistance to multiple classes of antibiotic
We explored the suitability of using the novel 4C−NH2 linker on the C8-position of the PBDs, which provides some advantages for the synthesis of the

Summary

Introduction

The resistance of pathogens to antibacterial agents has become a major global concern. Of great concern among all the bacteria that are developing resistance is a group of pathogens termed the ESKAPE pathogens, which are characterized by the rapid acquisition of resistance to multiple classes of antibiotic (with resistance to 3 or more classes referred to as multidrug resistance) These species are primarily associated with nosocomial infections especially among immunocompromised patients, and this has an additional economic impact upon the healthcare system.. A recent report from the World Health Organization has highlighted the limited number of drugs in the pipeline with only a few molecules in phase 2 and 3 of clinical development against ESKAPE pathogens; these are predominantly focused on Gram-positive species or are iterations of existing drugs (notably β-lactamase inhibitor combinations) This highlights the need to identify and evaluate new therapeutic options and/or to modify existing chemical scaffolds to obtain antibiotics with improved properties, and a number of agents developed through this approach are currently undergoing clinical trials.. Considering their mechanism of action, PBDs have been extensively studied as anticancer agents but relatively unexplored as antibacterial agents.− Different studies showed the possibility of synthesizing PBD analogues characterized by their high selectivity for particular DNA sequences, by modifying the C8 position substituent. For example, PBD−biaryl conjugates, a subclass of monomers with C8-subunits, have shown preferences for GC sequences.

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