Antibacterial antibiotics

The term “antibiotics” is used in the literature with different definitions. The industry mainly use it for antibacterial agents, but the definition that we prefer here, which was adapted from the original one coined by Waksman (1947), i.e., an antibiotic is “a chemical substance, produced by micro-organisms (including fungi), which has the capacity to inhibit the growth of and even to destroy bacteria and other micro-organisms”. The natural functions of antibiotics can easily be explained, resulting from the high competition between fungi, bacteria, and other organisms in substrates such as soil, dung and plant debris. If a given organism has acquired the ability to produce a certain secondary metabolite by which it can kill the competing organisms that dwell in the same habitat, it is considered to possess a selective advantage that ultimately increases its fitness (Shearer 1995). Therefore it should come as no surprise that one large experimental study concluded that the majority of filamentous fungi are able to produce antibiotic compounds (Bills et al. 2009). Bills and Gloer (2016) summarized numerous important facts concerning the current state of the art in research on fungal secondary metabolites and concentrated heavily on the biochemical and genetic background of their biosynthesis. We are currently living in the “post-antibiotic” era, where both, the numbers and percentages of multi-resistant bacterial and fungal pathogens against the established antibiotics are drastically increasing, while the number of new therapeutic agents and developmental candidates has decreased (Cooper and Shlaes 2011). The reasons for this development are manifold, but the phenomenon is primarily due to the fact that the majority of pharmaceutical companies have lost interest in Research and Development on natural products and/or given up their activities in the anti-infectives sector. Experts around the world are now giving warnings about the serious consequences that the lack of antibiotics—in particular against the multi-resistant Gram negative human pathogenic bacteria can have (Friedman et al. 2016). After two decades of neglect, efforts of both the private and the academic sector on the discovery of new antibiotics have substantially increased.

The pipeline for antibacterial antibiotics (Hesterkamp 2017) shows that there are still some compounds under development, but the majority of those have been optimised from old compounds with known modes of action by chemical modifications. Therefore, it is likely that the resistant pathogens will easily find a way to cope with the new products, once they have reached the market. The aforementioned mutilins, which are derived from fermentation of the basidiomycete Clitopilus passeckerianus and subsequent semisynthesis, therefore represent the “newest” compound class that has been registered as an antibacterial drug. A derivative, retapamulin (5), was launched for use as a topical antibiotic against skin infections, and several further derivatives are undergoing clinical trials as systemic antibiotics. In general, basidiomycete cultures are much more difficult to handle with respect to large scale production of secondary metabolites, since they grow rather slowly and often have low yields. For the production of pleuromutilin, however, Bailey et al. (2016) managed to increase the yields substantially after the transfer of the biosynthetic genes into a fast growing heterologous Aspergillus host, which can more easily be handled in the production process. This accomplishment can give rise to some hope that in the future, more of the hitherto neglected, unique biologically active metabolites of basidiomycetes can be made accessible to preclinical development.