Supercharged vancomycin to the rescue

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In a recent study published today in Nature Communications, researchers have re-engineered existing antibiotics to make them more powerful. Dr Mark Blaskovich and Professor Matthew Cooper led a research team to supercharge the old antibiotic vancomycin so it can tackle some of the world’s most dangerous superbugs. Their study highlights a new strategy that could potentially revitalize other antibiotics.

Pharmaceutical companies have departed the antibiotic discovery field because new antibiotics are difficult to find and provide little return on investment compared with other therapeutic treatments, such as cholesterol-lowering medications or anticancer drugs. One of the few approaches that has been successful in producing new antibiotics is to re-engineer existing drugs to overcome bacterial resistance.

First developed in 1958, vancomycin became one of the so-called ‘last resort’ antibiotics, reserved for the most dangerous infections when other antibiotics failed. Over the years vancomycin was increasingly used as a frontline therapy and, as a result, bacteria have becoming progressively resistant to it. The rise of these vancomycin-resistant bacteria during the past two decades, and the lack of new antibiotics to treat these deadly infections, stimulated the team to look at ways to revitalize this old antibiotic.

Molecular dynamics simulation of vancapticin sitting on a bacterial membrane surface, with insertion of the lipid tail into the membrane. Image courtesy of Prof Alan E Mark and Dr ZhiGuang Jia, The University of Queensland

Vancomycin is a member of the class of glycopeptide antibiotics. Unlike other classes of antibiotics containing multiple members (such as lactam antibiotics), there are very few glycopeptides used in the clinic. Vancomycin and teicoplanin were first used in the 1950s and 1980s, respectively, with three new semisynthetic derivatives recently approved: telavancin in 2009 and dalbavancin and oritavancin in 2014. These three new analogs had complex and extended development timelines, passing through multiple owners and delays before eventually reaching the market.

In their recent study published in Nature Communications, Blaskovich and colleagues have developed a more potent, more selective version of vancomycin, funded by a Wellcome Trust Seeding Drug Discovery Award and grants from Australia’s National Health and Medical Research Council. The team appended additional substituents to vancomycin’s core to selectively target additional binding interactions with bacterial membranes in preference to human cell membranes, creating a series of supercharged vancomycin derivatives termed vancapticins.

Over the course of 3 years the team made substantial progress in improving the vancapticins, creating over 300 analogs that varied the membrane-targeting components, while assessing not only antimicrobial activity, but their propensity to induce resistance and their drug-like properties. Promising lead compounds potentially suitable for progression into formal preclinical development have been identified, with improved potency compared with vancomycin in multiple in vivo infection models. The rebooted vancomycin compounds have the potential to treat infections caused by Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant (MDR) Streptococcus pneumoniae, and vancomycin-resistant Enterococci (VRE).

The vancapticins have successfully been scaled up on a multi-gram scale.

One question that has dogged this program from the beginning is how urgent is the need for more Gram-positive antibiotics. While the market for a new Gram-positive antibiotic is generally perceived to be poor, there was similar skepticism before the introduction of daptomycin, which then proceeded to achieve annual sales of over US$1 billion/year. Currently, there are significant incentives (such as CARB-X) for developing new Gram-negative antibiotics for drug-resistant infections, which indeed are desperately needed due to the empty clinical pipeline and the emergence of extreme drug-resistant strains resistant to all known antibiotics. However, this research team strongly believes that more effective Gram-positive therapies are still needed. Indeed, taking figures from the 2013 US CDC report on antimicrobial resistance, it is apparent that the number of infections caused by resistant strains of only two Gram-positive organisms (MRSA and MDR Streptococcus pneumoniae) dwarfs the number of resistant Gram-negative infections by >1,000,000– <50,000. This translates into a similar imbalance in the number of deaths, which are more than six-fold higher (18,000 vs 3200) for Gram-positive organisms. While it is unclear how many of these deaths could be prevented by more effective antibiotic treatment, improved therapies are obviously needed.

Drug development is normally focused on improving binding to a biological target, and rarely focuses on assessing membrane-binding properties. This study highlights that this approach can be very effective when the drug target is located in the membrane (the Lipid II precursor of bacterial cell wall peptidoglycan), enabling the vancapticins to have much greater potency, as well as additional mechanisms of action  by causing membrane disruption. The question now is whether the same strategy can be used to revitalize other antibiotics that have lost effectiveness against resistant bacteria.

The team believes the vancapticins are a promising solution to increasing Gram-positive bacterial resistance, but the biggest barrier to continuing their development is finding a viable commercial route.  This project has involved a large number of people across many institutions over the years, whose main motivation, like the antibiotic pathfinders in the 1940s, has been to prevent people from dying from bacterial infections. We hope that their efforts have not been in vain, and that the vancapticins will become another weapon in the arsenal against drug-resistant infections.

The research, published today in the journal Nature Communications, was supported by the Wellcome Trust, the world’s largest biomedical charity, and Australia’s National Health and Medical Research Council.

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Source: Blaskovich MAT, Hansford KA, Gong Y et al. Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria. Nat. Comms. 9(22) doi:10.1038/s41467-017-02123-w (2018)

 

 

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