This application seeks to establish a collaborative program in marine antibiotic drug discovery headed by William Fenical from the Scripps Institution of Oceanography in association with Victor Nizet from the Schools of Medicine &Pharmacy, both faculty researchers at the University of California, San Diego. The program capitalizes on the recent discovery that new, genetically-diverse and chemically-rich actinomycete bacteria, the classic resource for antibiotics, reside in deep-ocean sediments. The program emphasizes innovative immunological and virulence factor-based approaches in anti-infective drug screening coupled with tried and true whole cell bioassay methods for bacteriostatic and bactericidal activities. The overall goal of this research program is to merge the marine microbiology and natural products chemistry expertise of the Fenical lab with the molecular microbiology and infectious disease expertise of the Nizet lab to establish a unique and long-term collaboration to discover new antibiotics effective against drug-resistant bacterial and fungal pathogens. To achieve this goal, a step-wise discovery and development program will be set in place that emphasizes the discovery of new molecules with unprecedented structures and significant in vivo activity. The program will focus on screening marine actinomycete culture extract fractions (more than 3,500 per year) against drug-resistant human pathogens of immediate concern, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VREF), Pseudomonas aeruginosa, multi drug-resistant Acinetobacter baumannii, and fluconazole-resistant Candida albicans. In addition, innovative, non-cell-kill assays will be involved, which include inhibition of two critical virulence factors of the leading bacterial pathogens, the golden carotenoid pigment of S. aureus, the pore-forming cytolytic toxin streptolysin S of group A Streptococcus (GAS), as well as an assay to boost the host innate immune function via induction of the global transcriptional regulator HIF-1 in macrophages and neutrophils. New antibiotics will be isolated, structurally defined and screened in vitro against an expanded panel of more than 35 other human pathogens. When sufficiently potent antibiotics are defined, they will be advanced to murine in vivo assay systems for therapeutic efficacy in systemic and localized infection models for MRSA (for classical antibiotic), HIF-1 (innate immune enhancement or pigment inhibition agents) or GAS (for SLS inhibition agents) with which the Nizet laboratory has extensive experience. Up to ten of the most promising new antibiotics will also undergo a limited number of more advanced preclinical evaluations including acute mouse toxicity, kinetics of antimicrobial effect, capacity for resistance development, and post-antibiotic effect. Compounds that meet the stringent requirements to be considered drug candidates will be advanced to collaborating industries or developed within UCSD through spin-off projects.

Public Health Relevance

. The continued emergence of drug-resistant infectious diseases has created a National health care emergency to which the approximately 2 million people acquire bacterial infections in U.S. hospitals each year, and 90,000 die as a result;approximately 70% of those infections are resistant to at least one drug. This application establishes a collaborative program between laboratories with expertise in (A) marine science and natural product chemists and (B) bacterial pathogenesis and infectious disease. The team will discover and characterize novel antibiotics from deep ocean marine microbes that are effective against several drug-resistant bacterial and fungal pathogens, thus providing heath care practitioners with critical new approaches to infectious disease therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084350-03
Application #
7799728
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Hagan, Ann A
Project Start
2008-04-07
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$460,799
Indirect Cost
Name
University of California San Diego
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Hassan, Hossam M; Degen, David; Jang, Kyoung Hwa et al. (2015) Salinamide F, new depsipeptide antibiotic and inhibitor of bacterial RNA polymerase from a marine-derived Streptomyces sp. J Antibiot (Tokyo) 68:206-9
Hensler, Mary E; Jang, Kyoung Hwa; Thienphrapa, Wdee et al. (2014) Anthracimycin activity against contemporary methicillin-resistant Staphylococcus aureus. J Antibiot (Tokyo) 67:549-53
Degen, David; Feng, Yu; Zhang, Yu et al. (2014) Transcription inhibition by the depsipeptide antibiotic salinamide A. Elife 3:e02451
Jang, Kyoung Hwa; Nam, Sang-Jip; Locke, Jeffrey B et al. (2013) Anthracimycin, a potent anthrax antibiotic from a marine-derived actinomycete. Angew Chem Int Ed Engl 52:7822-4
Haste, Nina M; Thienphrapa, Wdee; Tran, Dan N et al. (2012) Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus. J Antibiot (Tokyo) 65:593-8
van der Westhuyzen, Renier; Hammons, Justin C; Meier, Jordan L et al. (2012) The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis. Chem Biol 19:559-71
Haste, Nina M; Farnaes, Lauge; Perera, Varahenage R et al. (2011) Bactericidal kinetics of marine-derived napyradiomycins against contemporary methicillin-resistant Staphylococcus aureus. Mar Drugs 9:680-9
Sun, Peng; Maloney, Katherine N; Nam, Sang-Jip et al. (2011) Fijimycins A-C, three antibacterial etamycin-class depsipeptides from a marine-derived Streptomyces sp. Bioorg Med Chem 19:6557-62
Haste, Nina M; Hughes, Chambers C; Tran, Dan N et al. (2011) Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 55:3305-12

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