Enhancing antifungal efficacy: leveraging PCA pathway inhibitors as antimicrobial adjuvants

The National Institute of Allergy and Infectious Diseases awarded Curatix, LLC $1,001,286 on July 14, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop potentiators of antimicrobial susceptibility (PAMs)—a novel class of antimicrobial adjuvant molecules that enhance the efficacy of existing FDA-approved antifungal drugs without exhibiting standalone antifungal activity.

Curatix is developing PAMs that target the pantothenate-CoA pathway, critical for coenzyme A and acetyl-CoA biosynthesis, to overcome azole and echinocandin resistance in fungal pathogens including Candida auris, Candida albicans, and Aspergillus fumigatus. The lead compound, PAMS3.1, has demonstrated in preclinical studies the ability to potentiate conventional antifungal drugs, enabling dose reduction and decreased toxicity while improving treatment outcomes. This combinatorial approach addresses the urgent clinical need created by rising antifungal resistance and the high mortality rates associated with invasive fungal infections.

Work is performed in Poquonock Bridge, Connecticut, with a period of performance through June 30, 2029. The award is a Phase II SBIR grant, as indicated by the R44 mechanism in the grant number.

Abstract

Fungal infections kill more than 1.5 million people worldwide each year. In the united states, invasive fungal infections (ifis) are a significant threat to immunocompromised patients, lengthen hospital stays and increase morbidity. Depending on the form of IFI, the mortality rates can be as high as 90%. The CDC currently classifies multi-drug-resistant candida auris as an urgent threat, and azole-resistant aspergillus species as an emerging threat. Common antifungal drugs (afds) include ergosterol biosynthesis inhibitors (ebis: azoles, allylamines, morpholines and polyenes) and echinocandins, are increasingly less effective due to rising resistance in fungal pathogens, coupled with their toxicity found in some drugs. This creates an urgent need for novel antifungal strategies to overcome these limitations and improve patient outcomes. Curatix presents a revolutionary approach to antifungal therapy through its potentiators of antimicrobial susceptibility (pams), a novel class of adjuvant-like molecules. Though pams exhibit no standalone antifungal activity, they dramatically enhance the efficacy of existing FDA-approved antifungal drugs when used in combination. Targeting the pantothenate- COA pathway (PCA pathway), which is critical for coenzyme a (COA) and acetyl-COA (accoa) biosynthesis, pams potentiate the activity of conventional drugs, significantly improving treatment outcomes. This combinatorial approach not only overcomes drug resistance but also enables dose reduction, thereby decreasing drug toxicity and cost, representing a pivotal advancement in the fight against life-threatening fungal infections. Our lead compound, PAMS3.1, has shown strong potential in preclinical studies, enhancing the efficacy of antifungals against candida auris, candida albicans, and aspergillus fumigatus, all of which are significant concerns in clinical settings. The proposed sbir will expand on these findings by evaluating 23 pams candidates against a broad spectrum of drug-sensitive and resistant fungal pathogens. Aim 1 will be testing of biological activities of 23 pams candidates in combination with antifungal drugs against drug-sensitive and drug-resistant strains of fungal pathogens and assessing their ability to potentiate antifungal drugs. Aim 2 will focus on in vitro cytotoxicity and pharmacological analysis of selected pams-drug combinations, while aim 3 will assess the in vivo efficacy of two leading combinations in mouse models and against clinical isolates. Successful completion of this program will provide critical data for advancing a pams-antifungal combination towards clinical trials. The commercialization of pams has the potential to capture a significant share of the antifungal market by offering a more effective and safer treatment option for ifis, addressing an urgent unmet medical need and paving the way for better patient outcomes worldwide.