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

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.

Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates

“…The C8-position of the A ring of PBD is the most preferred point of attachment of substituents within the compound's framework. Several chemical scaffolds, including heterocyclic polyamides [13][14][15], biaryl-units [16], benzofused rings [17] and quinazolinone [18] rings have been linked to the C8 position of PBD monomer producing compounds with improved DNA-sequence selectivity [13,16], and antimicrobial [19,20], anticancer [16] and antitubercular [21][22][23] activities compared to the PBD unit alone. The shape and physicochemical properties of C8-substituents have a direct effect on the cytotoxicity of the PBD-conjugates and their ability, or inability, to interact with the DNA-minor groove and inhibit transcription factors activity [13].…”

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

“…The C8-linked PBDs have been recently reported as DNA gyrase inhibitors . This was further explored by docking compounds 7 and 8 with the bacterial gyrase from S.…”

“…Pyrrolobenzodiazepines (PBDs) are naturally occurring molecules produced by Streptomyces bacteria whose family members include anthramycin and tomaymycin. , PBDs have a soft N10–C11 imine electrophile that can covalently bond to guanine bases . They have been extensively studied as anticancer agents − and, more recently, a large number of PBDs are being clinically evaluated as payloads for antibody drug conjugates (ADCs) demonstrating the broad therapeutic utility of this chemical class. , We recently described a series of C8-linked PBD monomers that showed activity against Gram-positive MDR strains, , which were able to inhibit Staphylococcus gyrase in a biochemical assay. It has been reported in the literature that the reason PBDs are only active against Gram-positive bacteria is due to their inability to cross Gram-negative membranes .…”

Antibiotic-in-Cyclodextrin-in-Liposomes: Formulation Development and Interactions with Model Bacterial Membranes

“…This study focuses on a novel antimicrobial agent, PPA148, belonging to the pyrrolobenzo­diazepine (PBD) group of anticancer and antimicrobial drugs (Figure and Supporting Information Table S1). PBDs are naturally occurring sequence-specific DNA minor groove binding agents produced by Streptomyces bacteria, which have been evaluated as potential antibacterial agents in recent years. − PBDs have shown promising activity against Gram-negative bacteria among the so-called ESKAPEEs, a group of pathogens of major clinical interest, in particular Acinetobacter baumannii and Klebsiella pneumoniae (with MICs < 2 μg/mL in each case) . PPA148 is a large, nonionic, poorly water-soluble drug, whose bactericidal activity is attributed to the inhibition of bacterial DNA gyrase, thus disrupting chromosomal replication and leading to cell death.…”