Optimized arylomycins: a new class of Gram-negative antibiotics?

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Researchers from Genentech (CA, USA) have identified what could be the first new class of antibiotics for Gram-negative bacteria in nearly 50 years from their research on optimization of the arylomycins.

With antimicrobial drug resistance a growing threat, the need for new drugs to treat Gram-negative infections is pressing. In this study, published recently in Nature, researchers have identified a molecule, termed G0775, which has potent, broad-spectrum activity against Gram-negative bacteria with a novel mechanism.

The team used a medicinal chemistry approach for optimization of the arylomycins – a class of natural products with weak activity and limited spectrum. This optimization process led to G0775, which was demonstrated to inhibit bacterial type I signal peptidase, an essential target, via a novel mechanism.

Moreover, G0775 was found to be over 500-times more potent against Gram-negative bacteria than a naturally occurring arylomycin. The researchers demonstrated G0775 had activity against common Gram-negative strains and in addition, when tested on a panel of drug-resistant strains provided by the Centers for Diseases Control and Prevention (GA, USA) it was effective against all of them.

The results were further verified in vivo where G0775 was observed to eradicate six strains of four different multi-drug resistant, Gram-negative infections in a mouse model.

Although further testing is necessary, this molecule and its novel mechanism could present a new class of antibiotics for this type of bacteria.

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Source: Smith PA, Koehler MFT, Giris HS et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018)

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