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The venom of the bee, Lasioglossum laticeps, contains three novel antimicrobial compounds known as lasioglossins, which have been structurally characterised by NMR spectroscopy. The compounds offer a new avenue for developing new antibiotics that might defeat drug-resistant bacteria. Almost as soon as the first antibiotic was administered, bacteria retaliated by quickly evolving resistance against the drugs. Today, there are strains of some pathogens that are capable of defeating all the common antibiotics. Drug researchers are constantly on the look out for novel molecular structures that might have unusual modes of action that might, temporarily at least, stave off the never-ending microbial onslaught. Vaclav Cerovsky of the Institute of Organic Chemistry and Biochemistry, at the Academy of Sciences of the Czech Republic and colleagues there and at the Charles University in Prague, Czech Republic point out that one intriguing avenue are the antimicrobial peptides (AMPs). Researchers have identified AMPs in almost all forms of life and often they represent the first line of defence against infection. Indeed, almost 1000 AMPs have been isolated from a wide range of organisms. The most well studied type of AMP are the linear, cationic alpha-helical peptides. These molecules have between 10 and 45 amino acids and are usually rich in hydrophobic and basic residues. The key characteristic of AMPs is that they are very different from conventional small-molecule antibiotics and have a significantly different mode of action to those compounds. The precise bacteriocidal mode of action is not fully understand but researchers think that these positively charged compounds attack the negatively charged bacterial cell envelope and disrupt its structure causing the bacterium to burst. The venom of wasps and ants are known to contain examples of AMPs. "Such peptides are good candidates as potential templates for the development of new and effective antibiotic peptides," explains Cerovsky. However, there is a major drawback to using these peptides as antibiotics: they also burst human cells, in particular red blood cells, and so are very toxic. However, there are so many potential sources of AMPs, that Cerovsky and colleagues reasoned that they ought to be able to find at least one that does not damage red blood cells but has antibiotic activity. They turned to the wild eusocial bee, L. laticeps, which occurs widely in Europe, nests in clay soil, but also frequents cobbled streets and gaps in walls. The team has now isolated three novel AMPs with relatively short amino acid chains from the venom of L. laticeps. Tests show them to be potent antibiotics against both Gram-positive and Gram-negative bacteria as well as being cytotoxic against cancer cells in the laboratory. However, these compounds have little effect on red blood cells or mast cells. The team searched sequence databases, including SwissProt and GenBank/EMBL Data Banks but found no common amino acid chains associated with known antimicrobial peptide data. They are confident in claiming the three lasioglossins from L. laticeps as new antimicrobial peptides. The team used NMR spectroscopy and circular dichroism to confirm an alpha-helical conformation for the peptides in a medium that mimics the surface of the bacterial cell membrane. NMR specialist Milos Budesinsky, one of Cerovsky's colleagues explains how the spectra revealed that these pentadecapeptides have a curved alpha-helical structure with a concave hydrophobic and convex hydrophilic side. It is this unusual bend in the peptides that the team believes is the secret to activity. Amino acid substitution studies, NOE effects, and molecular modelling point to other features, such as the N-terminal part for activity. Each of the newly discovered pentadecapeptides is active against a range of pathogens: Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa at micromolar concentration. These compounds therefore "represent an attractive subgroup of antimicrobial peptides that have potential to be further modified into therapeutics for treating certain infections," the team concludes.
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 NMR spectroscopy unravels peptide's antibacterial sting |
