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.

Highlights

  • The fight against bacterial infections is rapidly being lost as microbes develop multiple mechanisms to evade antibiotics

  • We recently described a series of C8-linked PBD monomers that showed activity against Gram-positive MDR strains,14,15 which were able to inhibit Staphylococcus gyrase in a biochemical assay

  • Three C8linked biaryl-PBD monomers with reported activity against Gram-positive species were selected as the starting point for the medicinal chemistry modification (Figure 1)

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Summary

■ INTRODUCTION

The fight against bacterial infections is rapidly being lost as microbes develop multiple mechanisms to evade antibiotics. 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. The aliphatic third ring containing C8-linked PBDs (compounds 3−17) showed notable improvement in activity against Gram-negative bacteria, except for P. aeruginosa, with MICs as low as 0.5 mg/L against MDR A. baumannii and K. pneumoniae strains. Against the Gram-positive species tested, all compounds, including the control PBD molecule, showed excellent activity, with MICs ranging from ≤0.03 to 2 mg/L (Table 2). In the case of K. pneumoniae NCTC 13368, which had a much higher intrinsic resistance to compound 7, only a small reduction in viable count was observed at 6 h, with bacterial numbers returning to the levels of the untreated control by 24 h, in two out of three replicate experiments When these bacteria were isolated, passaged 10× in the absence of selection and re-assayed, the MICs increased for both compound 7 (32 to ≥128 mg/L) and compound 8 The Tsx protein has previously been described as mediating resistance to the antibiotic albicidin in Klebsiella oxytoca. A second resistant NCTC 13368 isolate showed a SNP, leading to an amino acid change H50N in a predicted MerR family regulator (KPN_RS12075)

■ CONCLUSIONS
■ ACKNOWLEDGMENTS
■ REFERENCES
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