# Host Directed Orynotide for MDR Gram Negative Bacterial Infections

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $1,005,952

## Abstract

PROJECT SUMMARY
 The goal of this grant proposal is to advance the preclinical development of a novel macrocyclic peptide,
Orynotide™ MTD12813, for treatment of multidrug resistant (MDR) Gram negative bacterial infections, with the
initial focus being on infections caused by carbapenem-resistant Enterobacteriaceae (CRE). The emergence of
infections by multiple CRE pathogens has created an urgent public health threat, because carbapenems are
drugs of last resort for infections caused by an increasing fraction of MDR bacterial pathogens. Just two species,
Klebsiella pneumoniae and Escherichia coli, cause an estimated 140,000 nosocomial infections per year in the
United States alone, and many are carbapenem resistant. There is global consensus that new preventive and
therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. The
applicants, leaders in the field of θ-defensin biology, are responding to this need by developing Orynotides, a
new class of host-directed antimicrobial macrocyclic peptides bioinspired by the structural and biological
properties of theta (θ)-defensins, macrocyclic peptides expressed exclusively in Old World monkeys (but not
humans). Exploiting the pleiotropic host defense properties of θ-defensins, we produced a library of novel
Orynotides that includes several compounds that are highly effective in MDR Gram negative septicemia models.
Hit-to-lead studies identified MTD12813 as the lead Orynotide candidate for preclinical development as a first-
in-class immunotherapeutic agent for MDR Gram negative infections. In the mouse peritoneal sepsis model,
single dose administration of MTD12813 is highly effective (enhanced survival with concomitant bacterial
clearance) against multiple strains of CRE-K. pneumoniae and CRE-E. coli, and additionally was shown to be
effective in septicemia caused by MDR Acinetobacter baumannii. Consistent with the range of pathogens
against which MTD12813 is active in vivo, we showed that the peptide’s mode of action is immunotherapeutic,
promoting host-mediated bacterial clearance, stimulating phagocytosis and neutrophil recruitment, while
modulating levels of otherwise dysregulated proinflammatory cytokines. These data indicate that MTD12813 is
a novel immunotherapeutic agent effective in the treatment of Gram negative bacterial pathogens. The peptide
is readily manufacturable ( ~1.5 g on hand), highly stable in human plasma and whole blood, resistant to bacterial
proteases, and well tolerated when administered by numerous routes. In the proposed studies, we will advance
the preclinical characterization of MTD12813. Aim 1 studies will include production of GLP MTD12813 and other
critical reagents, pharmacokinetic (PK) and PK/pharmacodynamic analyses, and ADME studies. Aim 2 will focus
on illuminating mechanism(s) of action at the cellular and molecular level. Aim 3 objectives will include preclinical
non-GLP safety and toxicokinetic studies in rats and bea...

## Key facts

- **NIH application ID:** 10674221
- **Project number:** 1R01AI176543-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Justin Blaine Schaal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,005,952
- **Award type:** 1
- **Project period:** 2023-07-21 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10674221

## Citation

> US National Institutes of Health, RePORTER application 10674221, Host Directed Orynotide for MDR Gram Negative Bacterial Infections (1R01AI176543-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10674221. Licensed CC0.

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