Investigating the biosynthesis and mode of action of the formicamycin antibiotics

McDonald, Hannah (2022) Investigating the biosynthesis and mode of action of the formicamycin antibiotics. Doctoral thesis, University of East Anglia.

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Abstract

One of the most pressing issues of our time is antimicrobial resistance to currently used antibiotics. Therefore, new antibiotics are needed to ensure that we can continue to treat and prevent infections. Actinomycetes, such as Streptomyces, have predominately been at the forefront of antibiotic discovery for more than half a century and continue to provide new potential antibiotics. Streptomyces formicae is a new species which was isolated from the bodies and habitats of the fungus farming ants, Tetraponera penzigi, that has previously been found to produce a new class of antibiotics, the formicamycins. During this work, the biological activities, target(s) and mode of action of the formicamycins and their biosynthetic intermediates, fasamycins are investigated. We determined that both molecules are potent against Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Chemical analysis of S. formicae strains containing mutants within the formicamycin gene cluster allowed us to generate high yielding formicamycin strains and through heterologous expression of the for BGC we have identified several new glycosylated fasamycin congeners. Attempts to generate fasamycin of formicamycin resistant bacterial strains were unsuccessful, even after 40 days of sub-MIC exposure, we therefore determined that these compounds display a high barrier to resistance. Due to this high barrier to resistance and several lines of other in vitro evidence, we hypothesised that both fasamycin and formicamycin have multiple cellular targets. Previous work had identified the fasamycins as inhibitors of bacterial type II fatty acid synthesis (FAS-II), specifically FabF inhibitors, an essential elongation condensation enzyme within the FAS-II pathway. This work however reveals a second target of fasamycin and the first reported target of formicamycin, type II bacterial and archaeal topoisomerases. Overall, this work demonstrates that novel antibiotics can be found by exploring actinomycetes in under-explored environments.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Chris White
Date Deposited:	25 Apr 2023 07:21
Last Modified:	31 Dec 2023 01:38
URI:	https://ueaeprints.uea.ac.uk/id/eprint/91870
DOI:

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