Biology subjects

MacNair, C.

Publications and source records attributed to MacNair, C..

2 recordsLinked to original sources

bioRxiv2022

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug-resistant invasive non-typhoidal Salmonella (iNTS)

Bloodstream infections caused by invasive, non-typhoidal salmonellae (iNTS) are a major global health concern. These infections are especially problematic in sub-Saharan Africa, where the sequence type (ST) 313 of invasive non-typhoidal Salmonella Typhimurium (iNTS) is dominant. Unlike S. Typhimurium strains that cause mild gastroenteritis, iNTS strains are resistant to multiple first-line antibiotics and have higher extraintestinal invasiveness, limiting current treatment options. Here, we performed multiple small molecule screens under infection-relevant conditions to reveal chemical sensitivities in ST313 as entry points to drug discovery to combat the clinical burden of iNTS. By screening the invasive ST313 sequence type under host-mimicking conditions, we identified the antimicrobial activity of the nucleoside analog 3-azido-3-deoxythymidine, which required bacterial thymidine kinase activity for its antimicrobial activity. In a parallel macrophage-based screening platform, we also identified three host-directed compounds (amodiaquine, berbamine, and indatraline) that significantly restricted intracellular replication of ST313 in macrophages without directly impacting bacterial viability. This work provides evidence that despite elevated invasiveness and multidrug resistance, iNTS S. Typhimurium remains susceptible to unconventional drug discovery approaches.

microbiology↗

bioRxiv2022

Polynuclear ruthenium complexes are effective antibiotics against Pseudomonas aeruginosa

There is an urgent need to develop new antibiotics for the treatment of infections caused by drug-resistant Gram-negative bacteria. In particular, new and diverse chemical classes of antibiotics are needed, as most antibiotics in clinical development are derivatives of existing drugs. Despite a history of use as antimicrobials, metals and metal-based compounds have largely been overlooked as a source of new chemical matter for antibacterial drug discovery. In this work, we identify several ruthenium complexes, ruthenium red, Ru265, and Ru360, that possess potent antibacterial activity against both laboratory and clinical isolates of Pseudomonas aeruginosa. Suppressors with increased resistance were sequenced and found to contain mutations in the mechanosensitive ion channel mscS-1 or the colRS two component system. The antibacterial activity of these compounds translated in vivo to Galleria mellonella larvae and mouse infection models. Finally, we identify strong synergy between these compounds and the antibiotic rifampicin, with a dose-sparing combination therapy showing efficacy in both infection models. Our findings provide clear evidence that these ruthenium complexes are effective antibacterial compounds against a critical priority pathogen and show promise for the development of future therapeutics.

microbiology↗