New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

Abstract

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis , Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

Benzothiazole DNA gyrase inhibitors and their conjugates with siderophore mimics: design, synthesis and evaluation

“…The design of new DNA gyrase inhibitor-siderophore mimic conjugates started from our potent GyrB/ParE inhibitors A and B (Table 1) that exhibited antibacterial activity against G+ and G− ESKAPE pathogens, limited potential for resistance development and efficacy in in vivo infection models. 13,14,36,37 The cocrystal structures of benzothiazole GyrB inhibitors in complex with S. aureus GyrB showed that the pyrrolamide moiety forms two hydrogen bonds with Asp81 (S. aureus GyrB numbering) and crystal water molecule as well as an extensive network of hydrophobic contacts. The benzothiazole core is engaged in the formation of cation-p interaction with Arg84 and substitution at position 4 allows for improving the physico-chemical properties and binding affinity by formation of additional interactions in the lipophilic oor of the binding site.…”

“…1). 13,14,36,37 In the design of conjugates with siderophore mimics, we considered two different approaches. In the rst design strategy, the 6-carboxylic acid was reacted with the 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one or 2-(aminomethyl)-5hydroxypyridin-4(1H)-one to form the amide derivatives 10 and 12.…”

“…In our recent study, we also showed that benzothiazole-based GyrB inhibitors with potent activity against G− strains have a topological surface area (TPSA) of less than 120 Å 2 . 36,37 Replacement of the phenyl ring of inhibitor B (TPSA = 100.0 Å 2 ) by the oxygen-and nitrogen-rich siderophore mimic in 18b results in a signicantly higher TPSA of 149.4 Å 2 , which may be one of the reasons for the weaker antibacterial activity of 18b despite the presence of the siderophore mimic in its structure.…”

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens

“…During our ongoing research on DNA gyrase and Topo IV inhibitors, we discovered ATP-competitive benzothiazole scaffold-based inhibitors that display potent antibacterial activity against ESKAPE pathogens. − As a part of our hit-to-lead development stage, we expanded the chemical space of the benzothiazole-based series to the synthetically challenging C5 position of the benzothiazole ring. In this paper, we present new inhibitors with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and investigate their possible binding modes by a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling.…”

Physicochemical Properties, Antimicrobial activity and Docking Study of Carboxymethyl Cellulose (CMC)

“…In this article, morpholine derivatives, known for their robust antibacterial and antifungal properties, have garnered attention (Durcik et al 2023). These derivatives show activity against enzymes essential for DNA synthesis, along with in uencing cellular stress response, rendering them valuable for combating a wide spectrum of bacteria and fungi (Ohui et al 2019).…”