Antimicrobial resistance is a global threat, with the potential to cause up to 10 million deaths per year by 2050. Therefore, the need for new and effective therapeutics is urgent. Developing species-specific drugs may be one viable option.
Researchers can design structure-based drugs based on target orthologs, which are now available at high resolution. The current study focused on mapping lipoprotein signal peptidase II (LspA), an enzyme involved in lipoprotein posttranslational processing in bacteria.
LspA is an attractive drug target for several reasons. First, it has no mammalian equivalents, and its active site is available on the outer surface of the inner membrane. It is also required for full virulence of gram-positive bacteria and is a concern for resistance development.
Natural antibiotics, such as globomycin and myxovirescin, inhibit LspA during competition. Therefore, the Trinity College researchers presented a study that used the high-resolution crystal structure of LspA from methicillin-resistant S. aureus in complex with globomycin and myxovirescin with the goal of understanding the specific mechanisms of action for each antibiotic.
Globomycin is produced by at least five Streptomyces species (gram-positive, filamentous bacteria) whereas myxovirescin is produced by Myxococcus xanthus (phylum proteobacteria, gram-negative). Both bacterial species are found in soil but otherwise have very little in common. Inhibition of LspA by both secondary metabolites indicates convergent evolution with acquisition of similar form and/or function over time in organisms with distinct genetic origin.
"Specifically, we have discovered how evolution has led two completely different types of bacteria to figure out a way of making two very different antibiotics with which to fend off bacterial neighbours in precisely the same way," said senior study author Martin Caffrey, fellow emeritus in Trinity's School of Biochemistry and Immunology. "This is an exquisite example of molecular convergent evolution."
The biosynthetic machineries in both Myxococcus and Streptomyces are able to fabricate molecular features in globomycin and myxovirescin that mimic different components of natural substrates of LspA during proteolytic cleavage. Both molecules target the catalytic dyad aspartates of LspA, which when complexed contain a common spine of 19 contiguous atoms.
However, the formation of these complexes occurs by extremely different mechanisms. Globomycin approaches from one side of the substrate-binding pocket, while myxovirescin does so from the other.
"While the two antibiotics are chemically distinct -- one is a cyclic depsipeptide (globomycin), and the other a macrocyclic lactone (myxovirescin) -- remarkably they achieve the very same end of shutting down the production of key components of the cell envelope in other bacteria. This weapon thereby kills or weakens the other bacteria," Caffrey added.
One goal of this research is to understand how nature crafts unique structures with similar functions at the molecular level. These chemical blueprints (pharmacophores) can be leveraged to guide the design and development of new, more effective targeted drugs.
"Scientists have recently devoted a lot of effort to tackling open, 'undruggable' targets -- many of which lack the defined binding pockets where drugs can interact specifically to achieve the desired outcome," Caffrey said. "The bacterial cell wall target that takes center stage in our work likewise has an open binding surface but in its case nature has figured out at least two ways of targeting it with very high affinity using the natural antibiotics, globomycin and myxovirescin. And they do so in ways that are, at once, similar and distinct."
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