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

Pietro Picconi,Charlotte K Hind,Kazi S Nahar,Khondaker Miraz Rahman,Naima Saeed,Jessica Solomons,Bonnie Evans,Matthew E Wand,Lucia Di Maggio,J Mark Sutton,Shirin Jamshidi

doi:10.1021/acs.jmedchem.0c00328

Pietro Picconi, Charlotte K Hind + Show 9 more

Open Access

https://doi.org/10.1021/acs.jmedchem.0c00328

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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)

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