Lysostaphin
July 2009
PSI-SGKB [doi:10.3942/psi_sgkb/fm_2009_7]
Antibiotics are one of the major triumphs of twentieth century science, but unfortunately, the bacteria are fighting back. Drug-resistant strains are continually emerging as bacteria evolve and share new methods to shield their antibiotic-sensitive machinery, or destroy antibiotics directly. Today, we are searching for new approaches to fight our microscopic enemies using the tools of structural and molecular biology.
Magic Bullets
As with much of the earliest work in antibiotic discovery, researchers at the NYSGXRC are looking to the microbial world for leads. They have recently solved the structure of lysostaphin from the bacterium Vibrio cholerae. Like lysozyme, the original magic bullet explored by Alexander Fleming, lysostaphin is an enzyme that attacks the cell walls of bacteria. These cell walls are composed of long strings of sugars and amino acids, which are then crosslinked into a tough network that encloses the cell. Lysozyme and lysostaphin break linkages in this peptidoglycan network, and the cells burst under their own internal pressure.
Targeted Attack
Lysostaphin is a specialized killer, however. The crosslinks in the peptidoglycan come in many varieties. In some bacteria, the links are formed directly between amino acids in the peptidoglycan strands. In Staphylococcus aureus, however, a strand of five glycine amino acids is used as the linker. This is the weak point that is targeted by lysostaphin--it binds to the peptidoglycan sheath and clips these glycine crosslinkers.
Battling Infection
Lysostaphin is currently being tested as a possible treatment for infections by Staphylococcus infections. This includes topical formulations for treatment of infected wounds, as well as systemic formulations used in combination with antibiotics. Lysostaphin has been shown to be effective against antibiotic-resistant forms of the bacteria. But as with all interactions with bacteria, there is still the potential that they will develop ways to overcome it. Already, strains have been discovered that are less susceptible to lysostaphin, strains that either build a gluey polysaccharide capsule that shields their peptidoglycan, or strains that fortify the linkers in their peptidoglycan. The battle continues...
References
Ragumani, S., Kumaran, D., Burley, S. K. and Swaminathan, S. (2008) Crystal structure of a putative lysostaphin peptidase from Vibrio cholerae. Proteins 72, 1096-1103.
Kumar, J. K. (2008) Lysostaphin: an antistaphylococcal agent. Appl. Microbiol. Biotechnol. 80, 555-561.
Firczuk, M., Mucha, A. and Bochtler, M. (2006) Crystal structures of active LytM. J. Mol. Biol. 354, 578-590.
Bochtler, M., Odintsov, S. G., Marcyjaniak, M. and Sabala, I. (2004) Similar active sites in lysostaphins and D-Ala-D-Ala metallopeptidases. Prot. Sci. 13, 854-861.
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