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Principal Investigator: Gary A Jarvis
Organization: VETERANS AFFAIRS MED CTR SAN FRANCISCO
Fiscal Year: 2024
Funding agency: Veterans Affairs
The overall research program of the applicant has focused on the role of LOS and the innate immune
system and has shown that the degree of phosphorylation of the lipid A component is correlated with the
potential of the LOS to induce innate immune cytokine-mediated inflammation and, in general, with the severity
of Neisserial disease. Based on the results of these studies, recent work has undertaken the development of
potential therapeutics targeting gonococcal LOS as infections due to N. gonorrhoeae are a major cause of
morbidity with an estimated 850,000 cases in the U.S. and 87 million cases worldwide annually. Within the VA
Health Care System, cases of gonorrhea increased between 2013 and 2017 with the total number in that time
period at 10,587. Within the U.S. military, service members are a defined high-risk group for gonorrhea as
noted by the U.S. Preventive Services Task Force as the high-risk environment of active military service is
thought to increase risky behavior and, thus, the rate of sexually transmitted infections including gonorrhea. A
total of 27,658 cases of gonorrhea were identified among active duty personnel during FY 2007 to 2015 (222.7
per 100,000 military compared with 179.3 per 100,000 non-military in 2018). There is no vaccine to N.
gonorrhoeae and a great need for new antibiotics due to the alarming rise in multidrug-resistance (MDR),
which is making emergence of untreatable gonococcal infections a real prospect. Thus, there is a compelling
need for new antimicrobials for gonococcal infections.
To this end, the projects to be pursued during the proposed funding period of this SRCS award are as
follows: 1) LpxC inhibitors and cell-penetrating peptides; we recently reported that treatment of gonococci
with an inhibitor of LpxC, the enzyme that catalyzes the second step of lipid A biosynthesis, was bactericidal
for MDR and human challenge strains of gonococci and reduced cytokine induction without apparent human
cell cytotoxicity. Most recently, we evaluated the bactericidal potential of a 12 amino acid cell-penetrating
peptide (CPP) and found that it penetrated the bacterial membrane and was bactericidal for all multi-drug
resistant and human challenge strains of gonococci tested and reduced inflammatory cytokine induction and
prevented bacterial cell invasion of cervical epithelial cells. These novel data highlight LpxC inhibitors and
CPP as promising antimicrobials for N. gonorrhoeae and strongly support the hypothesis of this application that
inhibiting the biosynthesis of lipid A components with LpxC inhibitors and disrupting outer membrane integrity
with CPP will impact bacterial viability and host response to N. gonorrhoeae infection in vitro and in vivo, which
will have a therapeutic impact on infection outcomes. Translational studies of these two potential therapeutics
for gonorrhea will be the primary focus of the investigations proposed for the award period. 2) EptA
inhibitors; we will continue our collaboration with Drs. Charlene Kahler and Alice Vrielink of the University of
Western Australia in which we are targeting gonococcal EptA, the phosphoethanolamine transferase for lipid A,
with small molecule inhibitors to sensitize N. gonorrhoeae to killing by cationic antimicrobial peptides inside
neutrophils and reduce the induction of inflammatory cytokines. 3) Gonococcal survival in neutrophils; we
will continue our collaboration with Dr. Alison Criss of the University of Virginia to determine the impact of LOS
structural variation on the survival of gonococci in PMNs. 4) Gonococcal vaccine; in collaboration with Dr.
Peter Beernink of UCSF, we will develop native outer membrane vesicle vaccines from N. meningitidis strains
engineered to express potentially protective N. gonorrhoeae antigens.
Overall, the research proposed for the next SRCS funding period will continue to support the mission of VA
Healthcare through studies that will facilitate the translational development of potential therapeutics and
vaccines targeting gonorrhea, which is classified by CDC as an urgent public health threat due to the rapid
increase in the number of MDR isolates.
Terms: <Afghanistan><Amino Acids><Anabolism><Anti-microbial Cationic Peptides><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antigens><Antimicrobial Cationic Peptides><Armed Forces Personnel><Award><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><California><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Cervical><Classification><Collaborations><Communicable Diseases><Community Participation><Data><Development><Disease><Disorder><Drug Kinetics><Education><Educational aspects><Engineering><Environment><Enzyme Gene><Enzymes><Epithelial Cells><Faculty><Family><Female><Funding><Funding Agency><Funding Source><Generalized Growth><Gonococcal Infection><Gonococcus><Gonorrhea><Growth><Health Care Systems><Healthcare><Healthcare Systems><Heart Vascular><Human><Human Resources><Immune><Immune response><Immunes><Immunological response><In Vitro><In vivo analysis><Incidence><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Innate Immune System><International><Invaded><Investigation><Investigators><Iraq><Journals><Lead><Lipid A><Lytotoxicity><Magazine><Manpower><Marrow Neutrophil><Measurable><Mediating><Membrane><Meningococcus><Mentors><Microbicidal Cationic Proteins><Military><Military Personnel><Miscellaneous Antibiotic><Mission><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><N gonorrhea><N gonorrhoeae><N meningitidis><N. gonorrhea><N. gonorrhoeae><N. meningitidis><Neisseria><Neisseria gonorrhea><Neisseria gonorrhoeae><Neisseria meningitidis><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><Patient Care><Patient Care Delivery><Pb element><Peer Review><Penetration><Peptides><Pharmacokinetics><Phosphorylation><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Positive Test Result><Postdoc><Postdoctoral Fellow><Protein Phosphorylation><Public Health><Reporting><Research><Research Associate><Research Personnel><Researchers><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Risk Behaviors><Risky Behavior><Role><San Francisco><Scientist><Services><Severities><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Students><Survey Instrument><Surveys><Systematics><Testing><Therapeutic><Time><Tissue Growth><Toxic effect><Toxicities><Transferase><Transferase Gene><Translation Initiation><U.S. Preventative Services Task Force><U.S. Preventative Task Force><U.S. Preventive Services Task Force><U.S. Preventive Task Force><US Preventative Services Task Force><US Preventative Task Force><US Preventive Health Services Task Force><US Preventive Services Task Force><US Preventive Task Force><USPSTF><United States Preventative Services Task Force><United States Preventative Task Force><United States Preventive Services Task Force><United States Preventive Task Force><Universities><Vaccines><Variant><Variation><Venereal Diseases><Venereal Disorders><Venereal Infections><Vesicle><Veterans><Virginia><Virulence><Western Australia><Woman><Work><active duty><active service><adipogenesis><aminoacid><anti-microbial><antimicrobial><at risk behavior><bactericidal><bactericide><biosynthesis><care for patients><care of patients><career><caring for patients><circulatory system><conference><convention><cytokine><cytotoxicity><design><designing><developmental><ethanolamine phosphate><genital tract><health care><heavy metal Pb><heavy metal lead><high risk><high risk group><high risk individual><high risk people><high risk population><host response><immune system response><immunogen><immunoresponse><in vivo><in vivo evaluation><in vivo testing><inhibitor><lipid biosynthesis><lipogenesis><male><membrane structure><men><military member><military population><military service><mouse model><multi-drug resistant><multidrug resistant><murine model><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><patient population><personnel><phosphoethanolamine><phosphorylethanolamine><post-doc><post-doctoral><post-doctoral trainee><prevent><preventing><programs><reproductive tract><research associates><resistance strain><resistant strain><service member><sexually acquired infection><small molecular inhibitor><small molecule inhibitor><social role><summit><symposia><symposium><therapeutic target><translational study>