Antimicrobial Activity of Adenine-Based Inhibitors of NAD⁺-Dependent DNA Ligase

The relationship between enzyme inhibition and antimicrobial potency of adenine-based NAD⁺-dependent DNA ligase (LigA) inhibitors was investigated using a strain of the Gram-negative pathogen <i>Haemophilus influenzae</i> lacking its major AcrAB-TolC efflux pump and the Gram-positive pathogen <i>Streptococcus pneumoniae</i>. To this end, biochemical inhibitors not mediating their antibacterial mode of action (MOA) via LigA were removed from the analysis. In doing so, a significant number of compounds were identified that acted via inhibition of LigA in <i>S. pneumoniae</i> but not in <i>H. influenzae</i>, despite being inhibitors of both isozymes. Deviations from the line correlating antimicrobial and biochemical potencies of LigA inhibitors with the correct MOA were observed for both species. These deviations, usually corresponding to higher MIC/IC₅₀ ratios, were attributed to varying compound permeance into the cell

Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

AZD5099 (compound <b>63</b>) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound <b>63</b> showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, <b>63</b> could offer a novel treatment for serious issues of resistance to currently used antibacterials