Genentech develops antibiotic against multidrug resistant gram negatives
Genentech Inc. researchers have developed arylomycin derivatives with potent activity against Gram-negative bacteria, including multidrug resistant (MDR) strains. The small molecule could represent a notable step forward against Gram-negative bacteria, for which no new class of antibiotics has been approved in over 50 years.
Arylomycins are macrocyclic lipopeptides that target type I bacterial signal peptidase (SPase I) produced by both Gram-positive and Gram-negative bacteria; however, researchers have focused on developing arylomycins targeting Gram-positive bacteria. Previously no arylomycin had shown activity against Gram-negative MDR pathogens with a dual cell membrane.
In a Nature paper, the researchers optimized derivatives of arylomycin to cross the bacteria’s outer membrane and increase target affinity. In vitro, analog G0775 had minimum inhibitory concentrations (MICs) between 0.125 and 2 μg/ml against eight different Gram-negative species. Moreover, G0775 had MICs of ≤0.25 μg/ml against 90% of 49 MDR clinical isolates of Escherichia coli and Klebsiella pneumoniae; MICs of ≤4 μg/ml against 16 MDR strains of Acinetobacter baumanii; and MICs of ≤16 μg/ml against 12 MDR strains of Pseudomonas aeruginosa.
In mice with thigh infections of E. coli, K. pneumoniae, P. aeruginosa or A. baumanii, G0775 reduced bacterial loads in thigh muscle tissue compared with vehicle. The small molecule also decreased bacterial loads in the lungs of mice with K. pneumoniae lung infection and increased survival in a mouse model of K. pneumoniae peritonitis.
Genentech study authors Christopher Heise and Peter Smith told BioCentury the Roche (SIX:ROG; OTCQX:RHHBY) unit is continuing to develop arylomycin analogs to treat MDR infections, and has generated over 1,000 arylomycin analogs including G0775, but declined to offer details or timeline for development.
Roche has made several antibacterial deals of late. In October 2017, Roche partnered with Warp Drive Bio Inc. (Cambridge, Mass.) to discover and develop antibiotics using Warp Drive’s Genome Mining Platform. In April, Roche Ventures invested in Macrolide Pharmaceuticals Inc. (Watertown, Mass.), which is using its synthetic chemistry platform to develop a pipeline of macrolides from scratch with efficacy against drug-resistant Gram-negative pathogens.
Source: BioCentury
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