Essig A et al. 2014. Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis. Journal of Biological Chemistry. 289 (50): 34953-34964. doi: 10.1074/jbc.M114.599878
Antibiotics have proved fruitful in the clinic since the development of penicillin in the mid 1900’s. However, a growing problem is that bacteria have developed strategies of resistance to these antibiotics. Antimicrobial peptides (AMPs) secreted by fungi as a defensive strategy may be one avenue of developing new antibiotics that delay antibiotic resistance (Frey-Klett et al, 2011). Fungi and bacteria utilize defensive secretory strategies to guard their respective ecological niche in environments where they are co-localized (Scherlach). The secreted fungal AMPs can prove useful in the development of new antibiotics through mechanisms that may make it difficult for bacteria to develop resistance. In this study, the interaction of the fungal model organism Coprinopsis cineria with various bacteria was investigated in order to determine if the secreted AMPs could serve as useful antibiotics.
The researchers began their experimentation by co-incubating C. cineria with B. subtilis, P. aeruginosa, and E. coli and observed that the Gram-negative P. aeruginosa and E. coli demonstrated an inhibitory effect on the growth of C. cineria and C. cineria, in turn, demonstrated an inhibitory effect on the growth of the Gram-positive B. subtilis (Figure 1). In order to acquire a causative secretory agent of bacterial growth inhibition, C. cineria was grown in unchallenged minimal media. Proteins were extracted from the media and the CC1G_13813 protein (which they denoted copsin) was present in large concentration and produced a significant zone of inhibition in Gram-positive bacteria. The sequence and structure of copsin was determined through rt-PCR and NMR, and the structure revealed a highly stable architecture reminiscent of other known fungal defensins.
The activity of copsin was tested in another disk diffusion assay and a low minimum inhibitory concentration was observed in Gram-positive strains, implying that copsin was an effective agent for killing Gram-positive bacteria. Gram-negative bacteria were unaffected. The researchers then investigated a molecular target of copsin, and an obvious starting place was the bacterial cell wall. In a cellular localization assay, copsin was shown to bind extracellularly and was present in the same location as the known peptidoglycan inhibitor vancomycin (Figure 6). In order to determine a more specific target of copsin, binding assays with cell wall precursors were performed, and the results suggested a high affinity of copsin for both lipid I and lipid II.
This study highlights copsin as a potential future antibiotic. By extension, other fungal secretory elements could serve as additional therapeutic options, and this study promotes the promise that this investigation may hold. Additionally, the binding of copsin to lipid moieties (as opposed to a protein) reduces the likelihood of developing resistance in the short run. This is due to the fact that lipid moieties are synthesized by organic precursors as opposed to proteins, which are susceptible to mutation (Wright).
Frey-Klett K et al. 2011. Bacterial-fungal interactions: hyphens between agricultural, clinical, environmental, and food microbiologists. Microbiol. Mol. Biol. Rev. 75: 583-609. doi: 10.1128/MMBR.00020-11
Scherlack K et al. 2013. Molecular bacteria-fungi interactions: effects on environment, food, and medicine. Ann. Rev. Microbial. 67: 375-397. doi: 0.1146/annurev-micro-092412-155702
Wright, Gerard. 2015. An irresistible newcomer. Nature News and Views. 517: 442-444. doi: 10.1038/nature14193