New class of antibiotics discovered

The new compound can combat multidrug-resistant infections of Gram-negative bacteria, such as E. coli.

It’s been 50 years since a new antibiotic class with activity against Gram-negative bacteria has been approved. Now, at least, researchers have discovered one that could be a candidate and has performed well in preclinical research.

Gram-negative bacteria include the common pathogen Escherichia coli that can cause food poisoning, as well as multi-drug resistant bacteria that cause severe and often deadly infections. These Gram-negative bacteria all have a dual membrane that prevents antibiotics from accessing their targets.

Now researchers looked to a family of natural product inhibitors called arylomycin and discovered a synthetic derivative, called G0775, which can penetrate the outer membranes. G0775 was found to be effective against highly multidrug-resistant Gram-negative bacteria in multiple mouse models.

We spoke to two authors of the study Christopher Heise, PhD and Peter Smith, PhD from Genentech about the work. 

ResearchGate: How pressing is the need to develop new classes of antibiotics?

Christopher Heise & Peter Smith: Multidrug resistant (MDR) bacteria are spreading at alarming rates, and despite extensive efforts, no new antibiotic class with activity against Gram-negative bacteria has been approved in over fifty years. The situation is particularly worrisome for a group of Gram-negative bacteria found predominantly in hospitals. Without an entirely new way to combat them, gram-negative bacteria pose a serious threat to a highly vulnerable population.

RG: Why are Gram-negative bacteria so difficult to combat?

Heise & Smith: Gram-negative bacteria are characterized as possessing two distinct cellular membranes, the canonical cytoplasmic membrane and a second distinct membrane referred to as the outer-membrane. Due to the orthogonal property space of their constituents, the two membranes serve as a protective barrier, effectively functioning as a molecular sieve to preclude penetration of antibiotics into the bacterial cell. This double membrane system has stymied antibiotic discovery efforts and is largely the rationale for why no new class of antibiotic effective Gram-negative bacteria has been approved in over 50 years.

RG: Can you tell us briefly what you discovered?

Heise & Smith: One of the biggest challenges in creating new antibiotics for Gram-negative bacteria is that they possess two membrane layers, making it more difficult for antibiotics to penetrate and reach their targets. In this study, we used medicinal chemistry techniques to deconstruct arylomycin in order to develop select modified molecules, including G0775, that are orders of magnitude more potent than arylomycin and able to effectively penetrate the bacterial outer membrane to access signal peptidase.

The modified arylomycin analogue G0775 demonstrated potent activity against a panel of the deadliest Gram-negative bacteria found in U.S. hospitals collected by the Centers for Disease Control. This panel contains highly MDR strains known to resist numerous commercial antibiotics, including one such strain (CDC 0106) that is resistant to 13 different antibiotic classes. It also has remarkable efficacy against MDR Gram-negative infections in preclinical models. Importantly, the unique design of G0775 and mechanism of interaction with signal peptidase allows this molecule to circumvent known mechanisms of resistance that typically manifest in Gram-negative bacteria.

RG: What is the arylomycin class of natural products? Why did you decide to use these?

Heise & Smith: Arylomycins are a family of natural product inhibitors that are known to inhibit type 1 signal peptidase, an essential bacterial protein located on the outer surface of the inner membrane of Gram-negative bacteria. We initially selected the arylomycins due to their ability to cross the outer membrane and to inhibit signal peptidase.

RG: Could your study help develop new antibiotics?

Heise & Smith: Yes. The results from this study lay the scientific foundation for the discovery of a potential new class of antibiotics based on modified arylomycins. Our study showed that G0775 has broad preclinical activity against a diverse of Gram-negative bacteria and low vulnerability to spontaneous resistance, suggesting that optimized arylomycin analogues may represent a much-needed novel class of Gram-negative antibiotic.

RG: What’s next for your research? How long before you can test this in humans?

Heise & Smith: While this preclinical research is certainly exciting, it is too early to speculate on timing for future clinical development plans at this time.

Featured image by freestocks.org on Unsplash.

 

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