Targeted discovery of SPase inhibitors from marine bacteria
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: There exists a pressing need for the discovery of next generation antibiotics to treat the alarming rise in drug resistant bacterial infection. One important approach to antibiotic discovery is the identification of novel targets that can be exploited for the selective inhibition of bacterial growth without being toxic to the patient. One such target are bacterial proteins know as signal peptidases (SPases), which play a critical role in protein function and cellular distribution. Recognition that the antibiotic activity of the arylomycin class of natural products is due to the selective inhibition of bacterial SPases provides exciting validation for this target. The recently defined mechanism by which bacteria develop arylomycin resistance provides clear strategies to select for compounds that act on this target and possess broad-spectrum activity against both Gram-positive and Gram-negative pathogens. Thus, significant opportunities now exist for the pre-clinical development of the arylomycin class of antibiotics. This is a major objective of RQx Pharmaceuticals, which was recently founded in San Diego to develop SPase inhibitor antibiotics. Marine bacteria are poorly studied as a source of antibiotics, yet are yielding large numbers of new secondary metabolites. Thus there is a timely opportunity to incorporate new techniques in marine microbiology with efforts to discover antibiotic leads that act on specific bacterial targets. The proposed research will apply innovative chemical and biological screening approaches to the discovery of new SPase inhibitors from marine bacteria. A large collection of marine bacterial extracts will be screened for compounds in the arylomycin class. One hypothesis to be tested is that marine bacteria produce unique arylomycins in response to the survival pressures associated with life in the marine environment. Strains capable of producing compounds in this class will be cultured using a variety of fermentation techniques designed to yield new arylomycin analogs. In addition, a biochemical assay will be used to screen for new compounds that inhibit SPase activity. Through a close collaboration with RQx Pharmaceuticals, the corporate sponsor of this application, we propose to screen, isolate and structurally characterize new SPase inhibitors from marine bacteria. This collaboration presents a unique opportunity to develop an antibiotic discovery program around a new biological target through the exploitation of a poorly studied biological resource. Merging the corporate sponsor’s expertise in antibiotics with the rich collection of marine bacteria maintained in the PIs lab, we propose to discover new compounds in the arylomycin class in addition to new chemical scaffolds that exhibit SPase inhibition. This research presents a unique opportunity to fill the real need for the discovery of new antibiotics and to facilitate the development of a small, California-based biotechnology company.