Sialic acid analogs against multidrug-resistant gonorrhea

Active Project Grant Awarded Last action

Award ID
R01AI160247
Recipient
Awarding agency
Obligated
$12,304,866

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 93% complete
Originally
Funding
  • $10,988,109.00 Federal
  • $1,316,757.00 Non-federal
Place of performance
Worcester, MA 01655, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Gonorrhea is a major public health problem globally. About 87 million new cases of gonorrhea occur worldwide annually. In 2018, 583,405 cases were reported in the u.s, an 82.6% increase in disease incidence since the historic low in 2009. Concomitant infection with HIV and gonorrhea can increase rates of HIV transmission 5- fold. Dysbiosis of the vaginal microbiome (i.e., bacterial vaginosis (BV)) increases the risk of gonorrhea and HIV acquisition and transmission. Serious sequelae of gonorrhea in women include infertility, ectopic pregnancy and chronic pelvic pain. Neisseria gonorrhoeae (NG) has become resistant to almost every antibiotic in clinical use. Reports of resistance to ceftriaxone and azithromycin from almost every continent portends an ERA of untreatable gonorrhea. Development of novel therapies against NG is a global public health priority. Gonococci deploy a unique immune evasion strategy wherein IT caps its lipooligosaccharide (LOS) by a surface LOS sialyltransferase (LST) using host-derived CMP-NEU5AC. LOS sialylation enables NG to evade several aspects of host immunity, including complement and cationic antimicrobial peptides (camps). We discovered that gonococci FED with CMP-nonulosonates (CMP-nulos), such as CMP-legionaminic acid (CMP- LEG5,7AC2) and CMP-ketodeoxynonulosonate (CMP-KDN) cap their LOS with these nulos. Incorporation of nulos into NG LOS renders bacteria susceptible to complement and camps. Importantly, CMP-nulos significantly shorten the duration and burden of NG vaginal colonization in mice. Cathelicidin (a member of the camp family) played a key role in the MOA of CMP-nulos. Our efficacy, safety and stability studies have established CMP-LEG5,7AC2 and CMP-KDN as promising candidates for intravaginal delivery to prevent NG acquisition. In years 1-2 of aim 1, the NRC will produce CMP-nulos for all work in this proposal, perform a pharmacoeconomic analysis and assess scale-up. Process development, quality release assays, development of potency assays and stability in simulated genital tract fluids of the identified lead will follow in years 3-5. Aim 2 will elucidate factors that may affect safety efficacy of CMP-nulos. These include effects of CMP-nulos on growth and viability of favorable or unfavorable vaginal bacteria, the effects of sialidases elaborated by BV- associated pathogens and naturally-occurring anti-nulo antibodies on the efficacy of CMP-nulos in vitro and in vivo, examining cervicovaginal secretions for CMP-nulo hydrolase activity and testing the specificity of camps to bind nulo-containing glycans to refine the MOA of CMP-nulo against NG. Aim 3 will formulate the CMP-nulos into intravaginal rings (ivrs), perform PK studies in vitro and in a sheep model, and examine biofilm formation by vaginal microbiota on ivrs. Work in years 1-2 of the aims 1-3 will identify a single lead; works in years 3-5 will focus on further product development and IND-enabling activities. Aim 4 will verify activity of the lead CMP-nulo against genetically and geographically diverse NG isolates. Aim 5 includes regulatory guidance and oversight for all aims that will culminate in a pre-IND meeting with the FDA.

Transactions

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Amendment $1,316,757 $0
Original award $1,316,757 $1,316,757
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Subawards

Subrecipient Amount Awarded
National Research Council Of Canada The NRC’s Human Health Therapeutics (HHT) Research Centre hosts the largest R&D team dedicated to biotherapeutic development in Canada (~340 experts;… $1,010,803
University Of California, San Diego During the first 2 years of this project, UCSD investigators will help evaluate preclinical feasibility and effectiveness of CMP-NulO-based therapy for… $1,146,466
Oak Crest Institute Of Science The scope of work for the Oak Crest Institute of Science on this R01 project involves three primary objectives: (1) develop an intravaginal ring (IVR)… $1,429,463

Quick answers

Who received award R01AI160247?

R01AI160247 was awarded to University Of Massachusetts Medical School by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on April 20, 2021.

How much is award R01AI160247 worth?

$12,304,866 has been obligated on R01AI160247: $10,988,109 in federal funding and $1,316,757 in non-federal funding.

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