# Determinants and Mechanisms of Efficacy of Peptide Antibiotics as Novel Sepsis Therapy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $349,844

## Abstract

Project summary/Abstract
The premise of the proposal is that cationic antimicrobial peptides (AMPs) can be designed to enhance systemic
efficacy for sepsis treatment based on the unique properties to kill bacteria regardless of multidrug resistance
(MDR) as well as to attenuate inflammation mediated by endotoxin stimulation of toll like receptor (TLR) 4. This
will be accomplished using a series of rationally engineered libraries of novel peptide antibiotics (PAX) to
establish the distinction between structural determinants of antimicrobial potency and those of host toxicity.
Sepsis or SIRS (systemic inflammatory response syndrome) is defined as a “life-threatening organ dysfunction
caused by a dysregulated host response to infection.” Sepsis-related fatality rate is approximately 30% annually,
which may reach up to 50% in more severe cases. The development of multiple classes of antibiotics toward the
mid-20th century initially led to a sharp decline in sepsis-related mortality. However, persistent sepsis morbidity
and mortality, even with the use of effective antibiotics, is indicative of heightened immune responses and MDR.
The increased frequency of MDR bacteria has created an urgent need for the development of novel classes of
antibiotics with new antimicrobial mechanisms. In addition, sepsis has a complex pathophysiology that makes it
difficult to treat. By mitigating stimulation of inflammation via TLR4 signaling and eliminating the causative agent
(bacteria), AMPs has the potential to eradicate the problem by its root. Over the past decade we have developed
novel strategies to design and characterize cationic AMPs for treatment of infections associated with MDR
bacteria based on de novo engineered cationic antimicrobial peptides (eCAPs). The use of Trp substitution on
the hydrophobic side results in two lead peptides (WLBU2 and WR12) that retain broad-spectrum activity in
saline, acidic pH, and human plasma, indicating the specific roles of different amino acids in AMP function. Both
eCAPs were effective against 89-92% of a diverse panel of ESKAPE (MDR) pathogens compared to activity
against only 50% of these strains displayed by both the human AMP LL37 and colistin. WLBU2 also displays
systemic efficacy in a P. aeruginosa septicemia model, which dispels the notion that AMPs ought to be used
only topically to be effective. A single systemic dose of WLBU2 protects mice injected with an otherwise lethal
inoculum of P. aeruginosa. However, an important concern is a narrow therapeutic index [TI = maximum tolerated
dose (MTD)/minimum therapeutic dose (mTd)]) of 3-5 (mTd of 3-4mg/kg and MTD of 12-15mg/kg) of WLBU2,
which will be addressed in this proposed research. We hypothesize that AMPs can be designed for application
to sepsis treatment based on a rational framework for structure-function correlations by elucidating the unique
contributions of the cationic and hydrophobic contents to antibacterial selectivity, endotoxin neutralization, and
h...

## Key facts

- **NIH application ID:** 10218207
- **Project number:** 5R01GM125917-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Berthony Deslouches
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,844
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218207

## Citation

> US National Institutes of Health, RePORTER application 10218207, Determinants and Mechanisms of Efficacy of Peptide Antibiotics as Novel Sepsis Therapy (5R01GM125917-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218207. Licensed CC0.

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