UC San Diego

Drug-resistant pathogens throughout the world, in first and third world countries, create a continual burden on public health. With global emergence of multiply-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and parasites like Plasmodium falciparum, there is a distinct need for the development of novel anti-infectives to target these infections. Our data encompasses interdisciplinary links between pharmacology, natural product chemistry, infectious disease pathogenesis and innate immunity. We have (I) characterized novel antibiotics as new classical-type antibiotics, (II) identified a significant virulence factor, alpha-toxin, in MRSA and characterized its potential as a therapeutic target and (III) investigated a pathogen-specific cAMP-dependent protein kinase (PKA) regulatory subunit as a possible therapeutic target in the treatment of P. falciparum. From this multi-dimensional approach, we have identified potent antibacterial therapies. Our data highlights the ocean as an extremely rich resource of chemically diverse scaffolds. Here, we comprehensively characterize four marine-derived chemical scaffolds, marinopyrrole, napyradiomycin, etamycin and nosiheptide for their potent antibacterial activities against contemporary strains of multi-drug resistant MRSA. Further, in this work, we identify a potential MRSA virulence factor inhibitor. Diflunisal, a known and commonly used non-steroidal anti-inflammatory agent, was predicted via virtual screening to inhibit the production of a pore-forming S. aureus toxin. Our data emphasizes the potent anti-virulence properties of diflunisal and identifies a wide range of supplementary anti-bacterial and anti-virulence properties that could prove extremely useful in treating virulent and pathogenic MRSA infections. Finally, we investigate the PKA regulatory subunit of P. falciparum to identify pathogen-specific features that may be implicated in its roles in malarial parasite development, host invasion and pathogenesis. We conclude it to be a valid therapeutic target by identifying species-specific differences parasitic and mammalian isoforms that may prove useful in the development and engineering of therapeutic inhibitors. This work highlights three novel approaches to anti- pathogen research where we pinpoint valid therapeutic targets and potential therapies in the ongoing battle against emerging superbugs