Acurx Pharmaceuticals : ESCMID Poster Presentation “Preclinical Microbiome Evaluation of novel PolC-inhibitor compounds (Begum, et. al., April 2026)"

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Preclinical microbiome evaluation of novel PolC-inhibitor compounds Khurshida Begum1, Abdulwhab Shremo Msdi1, Chenlin Hu1, Neil Shaw, M Jahangir Alam1, Eugenie Basseres1, Taryn A. Eubank1, Xiang Y. Yu2, Lawrence I. Mortin2, Michael

Poster P2839 Abstract: 7529

H. Silverman2, and Kevin W. Garey1

1University of Houston College of Pharmacy; 2Acurx Pharmaceuticals, LLC

Send correspondence to: Abdulwhab Shremo Msdi, PharmD, BCIDP Email: [e-mail]

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BACKGROUND

METHODS

• PolC inhibition disrupts DNA replication in low GC-content Gram-positive bacteria, including priority pathogens such as Staphylococcus, Enterococcus, and Streptococcus species.1

• Ibezapolstat, a first-in-class PolC inhibitor for Clostridiodies difficile infection (CDI), demonstrated strong efficacy in phase 2 trial with microbiome preservation. 2, 3

• Next-generation PolC inhibtor compounds, ACX-978, ACX-801, and ACX-728, were developed to enhance systemic exposure and Gram-positive coverage.1

• However, their microbiome effects have not been elucidated

• Neutropenic CD-1 mice were infected intramuscularly with MRSA

• ACX compounds (100, 150 mg/kg, TID) and linezolid (100 mg/kg, BID) were administered orally beginning 1-hour post-infection (n=4/group)

• Controls included baseline and infection-only (placebo) groups

• Samples collected at 25 hours post-infection: plasma, feces, and thigh and colon tissue.

• Microbiome profiling: shotgun metagenomics (MetaPhlAn).

• Drug exposure quantified by LC-MS/MS.

RESULTS

Figure 1. Study Design

Figure 2. PolC inhibitors achieve good plasma and fecal levels at 24 hours

Figure 3. ACX compounds maintained higher microbial diversity and a community structure similar to baseline and distinct from linezolid Po Figure 4. PolC inhibition preserves Bacteroidota-dominate community structure (Left Panel) and function (Right Panel)

Figure 5. PolC inhibitors reduced MRSA burden in neutropenic mouse model

CONCLUSION

• PolC inhibitors demonstrate class-consistent microbiome preservation in concert with antibacterial activity (0.5 to 2.0 log10 reduction in CFU/g)

• Unlike linezolid, ACX compounds maintain Bacteroidota-dominant community structure and prevent Proteobacteria expansion.

• ACX-801 shows favorable systemic exposure with microbiome stability.

• PolC compounds represent a targeted strategy to treat resistant Gram-positive infections while preserving microbiome structure, minimizing downstream complications associated with antibiotic-induced dysbiosis

FUNDING

This study was funded by Acurx Pharmaceuticals, LLC

1. Wolfe TM, Jo J, Pinkham NV, Garey KW, Walk ST. The impact of ibezapolstat and other Clostridioides difficile infection-relevant antibiotics on the microbiome of humanized mice. Antimicrob Agents Chemother. Apr 2 2025;69(4):e0160424. doi:10.1128/aac.01604-24

2. Garey KW, McPherson J, Dinh AQ, et al. Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial. Clin Infect Dis. Sep 30 2022;75(7):1164-1170. doi:10.1093/cid/ciac096

3. Eubank TA, Jo J, Alam MJ, et al. Efficacy, safety, pharmacokinetics, and associated microbiome changes of ibezapolstat compared with vancomycin in adults with Clostridioides difficile infection: a phase 2b, randomised, double-blind, active-controlled, multicentre study. Lancet Microbe. Aug 2025;6(8):101126. doi:10.1016/j.lanmic.2025.101126