Lipopeptide antibiotics
Lipopeptide antibiotics are specialized molecules primarily produced by soil bacteria through nonribosomal pathways. Comprised of a fatty acid linked to a short chain of amino acids, these antibiotics are typically acidic and highly soluble in water. This class includes well-known antibiotics such as polymyxins, daptomycin, and echinocandins, which are particularly effective against gram-positive bacteria and require calcium for optimal antimicrobial activity.
Mechanistically, lipopeptide antibiotics disrupt microbial cell membranes, leading to increased permeability and subsequent cell death. For instance, polymyxins, discovered in the 1940s, are effective against various gram-negative bacteria and are employed in wound healing ointments and aerosol treatments for chronic infections. Daptomycin, effective against a range of gram-positive organisms, inhibits multiple cellular processes by binding to the bacterial membrane. Echinocandins, targeting fungal infections, prevent the formation of essential components in fungal cell walls.
With growing concerns around antimicrobial resistance, lipopeptide antibiotics have garnered renewed interest, particularly for treating serious infections when conventional therapies fail. Despite their efficacy, these compounds face challenges like poor solubility, tissue accumulation, and potential toxicity.
Subject Terms
Lipopeptide antibiotics
Definition
Lipopeptide antibiotics are molecules synthesized primarily by soil bacteria through nonribosomal metabolic pathways. These molecules typically consist of a fatty acid connected to a short linear or cyclic amino acid chain, and they are generally acidic, making them highly soluble in water. In addition to naturally occurring lipopeptide antibiotics, synthetic and semisynthetic analogs have been developed. This class of antibiotics includes polymyxins, daptomycin, and echinocandins. Many require calcium for maximum antimicrobial activity, and most are active against gram-positive but not gram-negative bacteria.
Mechanism of Action
Lipopeptide antibiotics bind to the cell membranes of specific microbial species and increase their permeability. As the cell membrane becomes less stable, the cell contents leak out, and the bacterium or fungus dies.
Specific Compounds
The best-studied lipopeptide antibiotics are polymyxin B and polymyxin E (colistin), which were discovered in the 1940s. Isolated from the soil bacterium Bacillus polymyxa, polymyxins are used to treat a variety of gram-negative organisms, including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, and Haemophilus influenzae. These compounds bind specifically to the lipopolysaccharide component of the outer membrane and disrupt the phospholipid bilayer. This detergent effect is effective against difficult-to-treat bacterial biofilms.
Commonly used commercial antibiotic ointments for wound healing combine polymyxin B with other antibiotics. An aerosolized form of polymyxin E is used to treat chronic P. aeruginosa infections in persons with cystic fibrosis. Polymyxin M (mattacin) is a later discovered polymyxin isolated from Paenibacillus kobensis. It is effective against both gram-positive and gram-negative bacteria.
Daptomycin, produced by Streptomyces roseosporus, is a lipopeptide antibiotic used for complicated skin and skin structure infections, bacteremia, and right-sided endocarditis. It binds to the bacterial cell membrane in a calcium-dependent manner, disrupting multiple aspects of cell membrane function. Daptomycin forms complexes with phosphatidylglycerol and cell wall precursors, interfering with cell wall synthesis. It also causes membrane depolarization and ion leakage, particularly potassium. These effects lead to the inhibition of various cellular processes, including protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, ultimately resulting in rapid bacterial cell death. Daptomycin appears to be effective against virtually all gram-positive organisms, but it is too large to cross the outer membrane of gram-negative bacteria. Resistance to daptomycin is rare, although it can develop.
Echinocandins are large natural and semisynthetic compounds effective against Candida and Aspergillus species. They include caspofungin, micafungin, and anidulafungin, which are administered as intravenous injections. These antifungal compounds prevent the synthesis of (1,3)-beta-D-glucan, an essential component of the fungal cell wall. The semisynthetic antifungal compound anidulafungin, derived from a fermentation product of A. nidulans, also targets (1,3)-beta-D-glucan synthesis.
Impact
Lipopeptide antibiotics are fast-acting bactericidal and antifungal compounds that do not tend to cause resistance. The problem of antimicrobial resistance and the lack of new antibiotics has renewed interest in lipopeptide antibiotics, and they are often used for serious infections when other therapies fail. Daptomycin in particular is effective against methicillin-resistant and vancomycin-resistant Staphylococcus aureus. The main limitations of these compounds are their poor solubility, their accumulation in tissues, and their risk of toxicity.
Bibliography
Cottagnoud, Philippe. "Daptomycin: A New Treatment for Insidious Infections Due to Gram-Positive Pathogens." Swiss Medical Weekly, vol. 138, 2008, pp. 93-99.
Fischbach, Michael, et al. "Antibiotics for Emerging Pathogens." Science, vol. 325, 2009, pp. 1089-1093.
Patel, Shivali, and Stephen Saw. "Daptomycin - StatPearls." NCBI, 17 Aug. 2024, www.ncbi.nlm.nih.gov/books/NBK470407. Accessed 31 Oct. 2024.
Pirri, Giovanna, et al. "Lipopeptides as Anti-infectives: A Practical Perspective." Central European Journal of Biology, vol. 4, 2009, pp. 258-273.
Raaijmakers, Jos M., et al. "Natural Functions of Lipopeptides from Bacillus and Pseudomonas: More than Surfactants and Antibiotics." FEMS Microbiology Reviews, vol. 34, no. 6, 2010, pp. 1037-1062, doi.org/10.1111/j.1574-6976.2010.00221.x. Accessed 31 Oct. 2024.
Slingerland, Cornelis J., and Nathaniel I. Martin. "Recent Advances in the Development of Polymyxin Antibiotics: 2010–2023." ACS Infectious Diseases, vol. 10, no. 4, Mar. 2024. ACS Publications, doi.org/10.1021/acsinfecdis.3c00630. Accessed 31 Oct. 2024.
Wiman, Emanuel, et al. "Development of Novel Broad-spectrum Antimicrobial Lipopeptides Derived from Plantaricin NC8 β." Scientific Reports, vol. 13, no. 1, 2023, pp. 1-16, doi.org/10.1038/s41598-023-31185-8. Accessed 31 Oct. 2024.