No abstract

We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

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.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a potentially fatal respiratory disease. Although it is most common in the Arabian Peninsula, it has been exported to 17 countries outside the Middle East, mostly through air travel. The Risk Assessment Guidelines for Infectious Diseases transmitted on Aircraft (RAGIDA) advise authorities on measures to take when an infected individual travelled by air. The aim of this systematic review was to gather all available information on documented MERS-CoV cases that had travelled by air, to update RAGIDA. The databases used were PubMed, Embase, Scopus and Global Index Medicus; Google was searched for grey literature and hand searching was performed on the EU Early Warning and Response System and the WHO Disease Outbreak News. Fortyseven records were identified, describing 21 cases of MERS that had travelled on 31 flights. Contact tracing was performed for 17 cases. Most countries traced passengers sitting in the same row and the two rows in front and behind the case. Only one country decided to trace all passengers and crew. No cases of in-flight transmission were observed; thus, considering the resources it requires, a conservative approach may be appropriate when contact tracing passengers and crew where a case of MERS has travelled by air.