Abstract
BackgroundWith the steady increase of antibiotic resistance, several strategies have been proposed in the scientific community to overcome the crisis. One of many successful strategies is the re-evaluation of known compounds, which have been early discarded out of the pipeline, with state-of-the-art know-how. Xanthoepocin, a polyketide widespread among the genus Penicillium with an interesting bioactivity spectrum against gram-positive bacteria, is such a discarded antibiotic. The purpose of this work was to (i) isolate larger quantities of this metabolite and chemically re-evaluate it with modern technology, (ii) to explore which factors lead to xanthoepocin biosynthesis in P. ochrochloron, and (iii) to test if it is beside its known activity against methicillin-resistant Staphylococcus aureus (MRSA), also active against linezolid and vancomycin-resistant Enterococcus faecium (LVRE)—a very problematic resistant bacterium which is currently on the rise.ResultsIn this work, we developed several new protocols to isolate, extract, and quantify xanthoepocin out of bioreactor batch and petri dish-grown mycelium of P. ochrochloron. The (photo)chemical re-evaluation with state-of-the-art techniques revealed that xanthoepocin is a photolabile molecule, which produces singlet oxygen under blue light irradiation. The intracellular xanthoepocin content, which was highest under ammonium-limited conditions, varied considerably with the applied irradiation conditions in petri dish and bioreactor batch cultures. Using light-protecting measures, we achieved MIC values against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which were up to 5 times lower than previously published. In addition, xanthoepocin was highly active against a clinical isolate of linezolid and vancomycin-resistant Enterococcus faecium (LVRE).ConclusionsThis interdisciplinary work underlines that the re-evaluation of known compounds with state-of-the-art techniques is an important strategy in the combat against multiresistant bacteria and that light is a crucial factor on many levels that needs to receive more attention. With appropriate light protecting measures in the susceptibility tests, xanthoepocin proved to be a powerful antibiotic against MRSA and LVRE. Exploring the light response of other polyketides may be pivotal for re-introducing previously discarded metabolites into the antibiotic pipeline and to identify photosensitizers which might be used for (antimicrobial) photodynamic therapies.
Highlights
With the steady increase of antibiotic resistance, several strategies have been proposed in the scien‐ tific community to overcome the crisis
Vrabl et al Microbial Cell Factories (2022) 21:1 tests, xanthoepocin proved to be a powerful antibiotic against methicillin-resistant Staphylococcus aureus (MRSA) and linezolid and vancomycin-resistant Enterococcus faecium (LVRE)
The initial aim of our work was (i) to explore the physiological prerequisites triggering the production of this metabolite, (ii) to isolate larger quantities of xanthoepocin to develop a suitable routine quantification method, and (iii) to perform an in-depth chemical characterisation that goes beyond the initial study of Igarashi et al [11]. (iv) Last but not least, we were interested if the reported bioactivity against MRSA [11] can be verified and if xanthoepocin is active against multiresistant Entercoccus faecium, which is one of the leading causes of nosocomial infections [32]
Summary
With the steady increase of antibiotic resistance, several strategies have been proposed in the scien‐ tific community to overcome the crisis. One other promising strategy is reexamining already known microorganism-derived antibacterial natural products, which were formerly excluded in the first stages from the screening process because they did not meet criteria like broad spectrum activity, efficacy, stability, or lack of cytotoxicity [2,3,4]. Most of these compounds were never explored in more depth again [4] and ended up on the “dusty shelves” of universities or pharmaceutical companies [2]. Other recent findings, such as the reexamination of γ-actinorhodin, underline this approach’s potential further [3]
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