Attacking drug-resistant infections by exploiting bacterial weak spots

26 November 2019

Arlene Weintraub / FiercePharma

The world’s most vexing infectious bacteria—Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae among them—are quickly becoming resistant to available antibiotics. Now, two research teams are proposing entirely new methods for attacking these bugs, not by killing them directly but rather by taking advantage of structural weaknesses in ways that make it impossible for the bacteria to survive.

Researchers led by McMaster University in Canada zeroed in on methicillin-resistant staph (MRSA). They screened 45,000 small molecules and hit upon one that works by lessening the ability of MRSA to tolerate an immune attack. They described the discovery in the journal Nature Chemical Biology.

The antibiotic, which the team dubbed MAC-545496, uncouples MRSA from glycopeptide resistance-associated protein (GraR). This protein normally shields MRSA from external threats, which allows the bacterium to become resistant to front-line antibiotics. Without GraR, the bug becomes much more vulnerable to immune clearance, the researchers said.

“This antimicrobial has a very exciting mode of action, kind of like hitting many birds with one stone,” said senior author Eric Brown, Ph.D., professor of biochemistry and biomedical sciences at McMaster, in a statement.

A novel peptide could offer a new way to treat gram-negative bacteria like E. coli, suggests an international team of scientists from Justus Liebig University Giessen in Germany, Northwestern University and other institutions. Their approach focuses on disrupting the external membrane that protects these bugs from external attacks.

The peptide, called darobactin, works by binding to the protein BamA, which resides on the external membrane of gram-negative bacteria. This prevents the bugs from establishing an intact external membrane, which in turn causes them to die, the researchers reported in the journal Nature.

“It is particularly interesting to note that this previously unknown weak point is located on the outside of the bacteria where substances can easily reach it,” said co-author Till Schäberle of JLU’s Institute of Insect Biotechnology, in a statement.

The team discovered darobactin by studying insect-pathogenic nematodes, which are parasites that multiply in the larva of insects. They screened extracts from the parasites to test the ability to combat E. coli, eventually landing on darobactin.

Schäberle and colleagues are now embarking on further research into darobactin. They plan to generate analogs of the substance that could be suitable for mass production, they said.

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