Ibezapolstat

点击蓝字 关注我们 投 医 问 药 Summary PolC 抑制剂是一类极具潜力的新型抗革兰氏阳性耐药病原体药物，首个此类药物已进入后期临床开发，但这类抑制剂发挥活性的结构基础、选择性机制及耐药性产生的关键位点仍未明确，限制了其进一步优化与研发。 2025 年 11 月 6 日，莱顿大学医学中心的 Meindert H. Lamers 和 Wiep Klaas Smits 团队在《Nature Communications》发表题为 “A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens”（《一种独特的抑制剂构象选择性靶向革兰氏阳性优先病原体的 DNA 聚合酶 PolC》）的研究论文。研究团队通过冷冻电镜技术解析了屎肠球菌 PolC 与 DNA、伊贝扎泊司他及新型抑制剂 ACX-801 的复合物结构，发现抑制剂通过独特的非平面构象在 PolC 中诱导形成结合口袋，与 DNA 形成碱基配对并竞争 dGTP 结合；鉴定出苯丙氨酸 1276 是关键敏感性决定因子，其突变会导致耐药性；同时证实结合口袋关键残基在革兰氏阳性病原体中高度保守，保障了抑制剂的选择性，为新型抗菌药物研发提供了分子基础。 欢迎关注公众号并设置星标 发送日期如20251107获取原文 Highlights 伊贝扎泊司他和 ACX-801 两种 PolC 抑制剂均通过与 DNA 形成碱基配对，在活性位点与 dGTP 竞争，发挥抗菌作用 抑制剂采用独特的非平面构象，可在 PolC 中诱导形成包含四个芳香族残基的结合口袋 苯丙氨酸 1276（艰难梭菌中为 F1258）是 PolC 抑制剂的关键敏感性决定因子，其突变会导致耐药性 PolC 抑制剂结合口袋的关键残基在革兰氏阳性优先病原体中高度保守，而在革兰氏阴性菌的 DnaE 型聚合酶中无结构同源物，保障了抑制剂的选择性 结构分析为合理设计针对 MRSA、VRE、艰难梭菌等耐药病原体的新型 PolC 抑制剂提供了分子基础 01 ｜INTRODUCTION 抗生素耐药病原体的威胁迫切需要开发作用机制新颖的抗生素，以靶向细菌生存必需的未被充分利用的生物学过程，例如 DNA 复制。细菌复制型 DNA 聚合酶属于原核生物特有的 C 家族聚合酶，由于其与真核生物对应物结构差异显著，成为理想的药物靶点。C 家族聚合酶具有 DNA 聚合酶典型的右手结构模体，其中拇指域和手指域负责定位 DNA 和进入的核苷酸（dNTP），而手掌域催化与模板 DNA 链互补的核苷酸掺入。C 家族聚合酶可进一步分为 PolC 型（Pol IIIC）和 DnaE 型聚合酶。在低 GC 含量的革兰氏阳性菌（厚壁菌门）中 —— 包括金黄色葡萄球菌、链球菌、艰难梭菌和肠球菌等优先病原体 ——PolC 作为主要的进行性酶负责大部分 DNA 合成，而 DnaE 同源物被认为参与后随链 DNA 合成。相比之下，革兰氏阴性菌和高 GC 含量的革兰氏阳性菌没有 PolC 同源物，而是采用 DnaE 型聚合酶作为主要的复制型 DNA 聚合酶。DnaE 和 PolC 之间的结构差异为选择性靶向提供了机会。因此，针对性抑制 PolC 有望成为一种治疗革兰氏阳性病原体感染的有效方法，同时最大程度减少对不含 PolC 生物的影响。 伊贝扎泊司他（IBZ）是由 Acurx 制药公司开发的首个 N²- 取代鸟嘌呤类抗生素，靶向 PolC 聚合酶，目前正准备进入 III 期临床试验。该药物被开发用于治疗艰难梭菌感染（CDI），这是医疗相关腹泻的最常见原因。艰难梭菌感染负担较重，部分原因是初始临床治愈后频繁复发。伊贝扎泊司他对多种艰难梭菌分离株具有活性，包括对临床常用抗菌药物敏感性降低的菌株，且目前尚未有预存耐药性的报道。重要的是，在 II 期临床试验中，接受伊贝扎泊司他治疗并治愈的患者在治疗后随访期间未观察到复发。伊贝扎泊司他的鸟嘌呤碱基部分表明其可作为 dGTP 竞争剂，将 PolC 捕获在可逆的失活状态并停滞复制叉。值得注意的是，芳香族侧链（伊贝扎泊司他中的 3,4 - 二氯苄基）被认为对特异性抑制 PolC 进而靶向革兰氏阳性菌至关重要。然而，目前尚未有 PolC 与抑制剂结合的结构报道，其作用机制的结构基础仍不明确。 研究团队解析了耐万古霉素屎肠球菌（VRE）PolC 与伊贝扎泊司他以及新型 PolC 抑制剂 ACX-801 形成的复合物冷冻电镜结构。研究团队的结构显示，鸟嘌呤碱基或其类似物与 DNA 模板链中的互补 dCMP 形成碱基配对，而 N² 连接的芳香族部分与碱基平面呈约 90° 角，插入一个包含四个芳香族残基的抑制剂诱导结合口袋中。细胞和生化分析表明，四个芳香族残基中的苯丙氨酸 1276（艰难梭菌中为 F1258）是驱动对伊贝扎泊司他和 ACX-801 产生耐药性的突变热点。该研究为合理开发用于治疗革兰氏阳性优先病原体感染的改良抑制剂奠定了基础。 02 ｜RESULTS 研究人员通过微量肉汤稀释法测定了 46 种 ACX 系列化合物对多种细菌的最低抑菌浓度（MIC），发现该类化合物对 VRE、MRSA 等革兰氏阳性病原体具有选择性抑制活性，对大肠杆菌等革兰氏阴性菌无活性；凝胶迁移实验和实时聚合酶活性测定证实，伊贝扎泊司他和 ACX-801 可有效抑制屎肠球菌 PolC 的聚合酶活性，其中 ACX-801 的 IC₅₀值为 5.8μM，抑制活性优于伊贝扎泊司他（12.3μM）；且两种抑制剂对革兰氏阴性菌的 DnaE 型聚合酶无显著抑制作用，证实了其靶向选择性。 图1 PolC 抑制剂选择性抑制革兰氏阳性菌的复制型聚合酶 研究人员通过微量肉汤稀释法测定了伊贝扎泊司他和 ACX-801 对 VRE、MRSA、耐青霉素肺炎链球菌（PRSP）等革兰氏阳性优先病原体的 MIC 值，并与万古霉素、利奈唑胺等常用抗菌药物进行对比；结果显示，ACX-801 对 VRE、MRSA、PRSP 的抑制活性优于伊贝扎泊司他，MIC 值低至 0.25-1mg/L，且对常用抗菌药物耐药的菌株仍具有强效抑制作用；而两种抑制剂对革兰氏阴性菌大肠杆菌均无抑制活性（MIC>64mg/L），证实了其针对革兰氏阳性耐药病原体的抗菌特异性和应用潜力。 表1 核苷碱基类似物对革兰氏阳性优先病原体的抗菌特异性 研究人员通过单颗粒冷冻电镜技术，解析了屎肠球菌 PolC 的 apo 状态结构、与 ACX-801 结合的复合物结构（分辨率 2.8-3.2Å）以及与伊贝扎泊司他结合的复合物结构；结构显示 PolC 包含 OB 结构域、外切核酸酶结构域、PHP 结构域等多个功能域，符合 C 家族聚合酶的典型右手结构模体；抑制剂与 DNA 模板链的 dCMP 形成碱基配对，其 N² 连接的芳香族部分呈 90° 角插入 PolC 中诱导形成的结合口袋，该口袋由 H1185、F1276、H1280 和 Y1284 四个芳香族残基构成；F1276 在 apo 状态下会阻断结合口袋，结合抑制剂后向外移动以容纳抑制剂。 图2 屎肠球菌 PolC 与伊贝扎泊司他和 ACX-801 的冷冻电镜结构 研究人员通过序列比对和结构分析发现，构成 PolC 抑制剂结合口袋的四个芳香族残基在革兰氏阳性菌的 PolC 聚合酶中高度保守，而在革兰氏阴性菌的 DnaE 型聚合酶中，包含 H1185 的螺旋更短，且无结构同源物；Y1274 在 PolC 中与抑制剂的 R2 基团相互作用，而在 DnaE 型聚合酶中远离抑制剂结合口袋；这些结构差异解释了 PolC 抑制剂对革兰氏阳性菌的选择性抑制作用，且为抑制剂的特异性设计提供了结构依据。 图3 PolC 抑制剂选择性的结构解释 研究人员对筛选获得的屎肠球菌耐药菌株进行交叉耐药性检测，发现携带 PolC 突变（F1276I、F1276L、F1276S、A1281T）的菌株对多种 ACX 系列 PolC 抑制剂及伊贝扎泊司他均表现出交叉耐药性，MIC 值升高 8-64 倍；但这些菌株对利奈唑胺、达托霉素、奥马环素等作用机制不同的抗菌药物仍保持敏感，证实耐药性是特异性针对 PolC 抑制剂产生的，且未影响细菌对其他抗菌药物的敏感性。 表2 敏感性降低菌株对其他 PolC 抑制剂存在交叉耐药，但对不同作用机制的抗菌药物无交叉耐药 研究人员通过耐药突变筛选，发现屎肠球菌暴露于 ACX 系列化合物后，PolC 的 F1276 位点易发生突变（F1276I、F1276L、F1276S），这些突变会显著降低菌株对伊贝扎泊司他和 ACX-801 的敏感性；体外生化实验证实，F1276L 和 F1276S 突变会使 PolC 对伊贝扎泊司他的 IC₅₀值增加 48 倍以上，对 ACX-801 的 IC₅₀值也显著升高，但不影响 PolC 的基础聚合酶活性；在艰难梭菌中，F1258（对应屎肠球菌 F1276）的突变同样会导致耐药性；此外，A1281T 突变会降低 PolC 的聚合酶活性，但也会导致耐药性，且该位点在不同物种中功能保守。 图4 特定苯丙氨酸残基是 PolC 抑制剂的关键敏感性决定因子 03 ｜DISCUSSION 综上所述，该研究通过结构生物学、生物化学和遗传学等多学科手段，系统阐明了 PolC 抑制剂靶向革兰氏阳性病原体的分子机制、选择性基础及耐药性产生的关键因素。研究证实 PolC 抑制剂通过独特的非平面构象与 DNA 形成碱基配对，在活性位点与 dGTP 竞争，同时诱导 PolC 形成特异性结合口袋，其结合口袋的关键残基在革兰氏阳性优先病原体中高度保守，而在革兰氏阴性菌中无结构同源物，保障了抑制剂的靶向选择性。苯丙氨酸 1276 是抑制剂敏感性的核心决定因子，其突变会破坏与抑制剂的相互作用，导致耐药性，而 A1281T 突变则通过影响 PolC 活性或结合口袋构象产生耐药性。这些发现不仅解释了现有 PolC 抑制剂的作用模式，还为合理设计优化新型抑制剂提供了精确的结构模板，有助于解决 MRSA、VRE、艰难梭菌等耐药病原体带来的临床挑战，推动新型抗菌药物的研发进程。 References [1] Urem, Mia, et al. "A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens." Nature Communications, vol. 16, no. 9784, 2025, https://doi.org/10.1038/s41467-025-65324-8. [2] Antimicrobial Resistance Collaborators. "Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis." Lancet, vol. 399, 2022, pp. 629–655. [3] GBD 2021 Antimicrobial Resistance Collaborators. "Global burden of bacterial antimicrobial resistance 1990–2021: A systematic analysis with forecasts to 2050." Lancet, vol. 404, 2024, pp. 1199–1226. [4] Jernigan, J. A., et al. "Multidrug-resistant bacterial infections in U.S. hospitalized patients, 2012–2017." N. Engl. J. Med., vol. 382, 2020, pp. 1309–1319. [5] Bailey, S., et al. "The Structure of T. aquaticus DNA polymerase III is distinct from eukaryotic replicative DNA polymerases." Cell, vol. 126, 2006, pp. 893–904. [6] Evans, R. J., et al. "Structure of PolC reveals unique DNA binding and fidelity determinants." Proc. Natl. Acad. Sci., vol. 105, 2008, pp. 20695–20700. [7] Lamers, M. H., et al. "Crystal structure of the catalytic alpha subunit of E. coli replicative DNA polymerase III." Cell, vol. 126, 2006, pp. 881–892. [8] Smits, W. K., et al. "Clostridium difficile infection." Nat. Rev. Dis. Prim., vol. 2, 2016, p. 16020. [9] Butler, M. S., et al. "A review of antibacterial candidates with new modes of action." ACS Infect. Dis., vol. 10, 2024, pp. 3440–3474. [10] Ruggieri, F., et al. "Antibiotics with novel mode of action as new weapons to fight antimicrobial resistance." Eur. J. Med. Chem., vol. 256, 2023, p. 115413. [11] Baños-Mateos, S., et al. "High-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center." Nat. 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Pioneering data demonstrate that Acurx's U.S. and EU Phase 3-ready DNA pol IIIC inhibitor, ibezapolstat (IBZ), has unique selective antibacterial activity in the gut which spares beneficial bile acid-metabolizing bacteria The favorable gut bile acid profile contributes to ibezapolstat's anti-recurrence effect in patients with C. difficile Infection (CDI) New data presented on representative novel compounds from Acurx's DNA pol IIIC inhibitor preclinical pipeline provide initial evidence that microbiome selectivity, when compared to the comparator antibiotic, linezolid, may be a class effect Ibezapolstat has previously received FDA QIDP and Fast-Track Designation from FDA; Acurx's preclinical antibiotic candidates are FDA QIDP/Fast track eligible for systemic treatment of infections caused by other Gram-positive priority pathogens STATEN ISLAND, N.Y., Oct. 28, 2025 /PRNewswire/ -- Acurx Pharmaceuticals, Inc. (NASDAQ: ACXP) ("Acurx" or the "Company"), is a late-stage biopharmaceutical company developing a new class of antibiotics for difficult-to-treat bacterial infections. It announced today that a presentation was given by Michael Silverman, MD, FACP, Acurx's Medical Director, and Kevin Garey, PharmD, MS, FIDSA, Professor and Chair, University of Houston College of Pharmacy, Principal Investigator for microbiology and microbiome aspects of the ibezapolstat clinical trial program at the Infectious Diseases Society of America (IDSA) IDWeek™ 2025 Scientific Conference held on October 19-22, 2025 in Atlanta, GA. Acurx was one of five companies invited to present at the New Antimicrobials in the Pipeline session on October 20. The presentation entitled: First of a New Class of Antibiotics (DNA pol IIIC Inhibitors) Targeting CDC/FDA/WHO Priority Pathogens; Preparing for the Next Pandemic: Antimicrobial Resistance in Gram-positive Bacterial Infections. The Company's presentation included an update on ibezapolstat and its microbiome sparing properties. Also, presented were new colonic microbiome data from a mouse infection model showing a potential microbiome-sparing class effect of representative compounds from the Company's DNA pol IIIC inhibitor preclinical pipeline. In describing the work performed at his laboratory at the University of Houston, Dr. Garey stated: "Initial work on novel, lead DNA pol IIIC inhibitor compounds indicate that the positive microbiome-sparing results from our ibezapolstat studies may be a class effect. This is an important finding because microbiome sparing likely contributed to IBZs sustained efficacy in the Phase 2 trial where no patient cured of CDI experienced a recurrence. In our recent experiments, mice given the comparator antibiotic, linezolid, demonstrated an over-abundance of uncommon and harmful Gram-negative bacteria called Pseudomonadota, previously known at Proteobacteria. He further stated: "These data indicate a low probability for DNA pol IIIC inhibitors to increase the risk of causing a Clostridioides difficile infection, vancomycin-resistant Enterococcus, or other gut-microbiome related infections." Robert J. DeLuccia, Executive Chairman of Acurx, stated: "As leaders in the field in developing a class of antibiotics that effectively treat infections caused by Gram-positive priority pathogens, preserving the healthy microbiome is a hallmark of differentiation compared to currently available antibiotics." He further commented: "These new data providing initial evidence that microbiome selectivity may be a class effect has the potential to create a transformational paradigm shift for treatment of serious and potentially life-threatening infections. These include acute bacterial skin and skin-structure infections (including those caused by MRSA), community-acquired bacterial pneumonia, hospital and/or ventilator-associated bacterial pneumonia, anthrax and bacteremia with or without sepsis and/or infectious endocarditis; bone/joint infections & diabetic foot infections". The presentation is available on the Acurx Pharmaceuticals website at . About IDWeek and the IDSA The Infectious Diseases Society of America (IDSA) is a community of over 12,000 physicians, scientists and public health experts who specialize in infectious diseases. Our mission is to improve the health of individuals, communities, and society by promoting excellence in patient care, education, research, public health, and prevention relating to infectious diseases. IDWeek is the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). About Acurx Pharmaceuticals, Inc. and Its DNA pol IIIC Discovery Program Acurx Pharmaceuticals is a late-stage biopharmaceutical company focused on developing a new class of small molecule antibiotics for difficult-to-treat bacterial infections. The Company's approach is to develop antibiotic candidates with a Gram-positive selective spectrum (GPSS®) that blocks the active site of the Gram-positive specific bacterial enzyme DNA polymerase IIIC (pol IIIC), inhibiting DNA replication and leading to Gram-positive bacterial cell death. Its R&D pipeline includes antibiotic product candidates that target Gram-positive bacteria, including Clostridioides difficile, methicillin- resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), drug- resistant Streptococcus pneumoniae (DRSP) and B. anthracis (anthrax; a Bioterrorism Category A Threat-Level pathogen). Acurx's lead product candidate, ibezapolstat, for the treatment of C. difficile Infection is Phase 3 ready with plans in progress to begin international clinical trials. The Company's preclinical pipeline includes development of an oral product candidate for treatment of ABSSSI (Acute Bacterial Skin and Skin Structure Infections), upon which a development program for treatment of inhaled anthrax is being planned in parallel. DNA pol IIIC inhibitors have been clinically validated with the first-generation inhibitor ibezapolstat (IBZ), now entering Phase 3 clinical trials for Clostridioides difficile infection. IBZ has intended poor oral bioavailability and is only appropriate for treatment of gut-associated C. difficile infection. Acurx is advancing novel inhibitors for oral and IV administration for treatment of systemic infections caused by CDC-priority gram-positive pathogens. Furthermore, DNA pol IIIC inhibitors have a defined regulatory pathway with transformative clinical use potential. Acurx uses new AI-driven FEP technologies to rapidly identify and advance novel DNA pol IIIC inhibitors and deliver IND lead candidates representing a new class of systemic antibiotics in >30 years to treat infections caused by gram-positive bacteria. Acurx's proposed innovation offers a disruptive solution that delivers a therapeutic effect with high precision and minimal off-target effects. By leveraging structural insights gained through previous studies and utilizing new FEP studies along with AI/ML approaches, the Acurx program aims to produce a systemically active antibiotic with a new mechanism of action (MOA), no cross resistance with existing antibiotics, and a gut microbiome sparing property that potentially supports long-term dosing for serious infections such as prosthetic joint infection, bacteremia, and osteomyelitis. Acurx previously announced that it had received positive regulatory guidance from the EMA during its Scientific Advice Procedure which confirmed that the clinical, non-clinical and CMC (Chemistry Manufacturing and Controls) information package submitted to EMA supports advancement of the ibezapolstat Phase 3 program and if the Phase 3 program is successful, supports the submission of a Marketing Authorization Application (MAA) for regulatory approval in Europe. The information package submitted to EMA by the Company to which agreement has been reached with EMA included details on Acurx's two planned international Phase 3 clinical trials, 1:1 randomized (designed as non-inferiority vs vancomycin), primary and secondary endpoints, sample size, statistical analysis plan and the overall registration safety database. With mutually consistent feedback from both EMA and FDA, Acurx is well positioned to commence our international Phase 3 registration program. The primary efficacy analysis will be performed using a Modified Intent-To-Treat (mITT) population. This will result in an estimated 450 subjects in the mITT population, randomized in a 1:1 ratio to either ibezapolstat or standard- of-care vancomycin, enrolled into the initial Phase 3 trial. The trial design not only allows determination of ibezapolstat's ability to achieve Clinical Cure of CDI as measured 2 days after 10 days of oral treatment but also includes assessment of ibezapolstat's potential effect on reduction of CDI recurrence in the target population. In the event non-inferiority of ibezapolstat to vancomycin is demonstrated, further analysis will be conducted to test for superiority. About the Ibezapolstat Phase 2 Clinical Trial The completed multicenter, open-label single-arm segment (Phase 2a) study was followed by a double-blind, randomized, active-controlled, non-inferiority, segment (Phase 2b) at 28 US clinical trial sites which together comprise the Phase 2 clinical trial. This Phase 2 clinical trial was designed to evaluate the clinical efficacy of ibezapolstat in the treatment of CDI including pharmacokinetics and microbiome changes from baseline. from study centers in the United States. In the Phase 2a trial segment,10 patients with diarrhea caused by C. difficile were treated with ibezapolstat 450 mg orally, twice daily for 10 days. All patients were followed for recurrence for 28± 2 days. Per protocol, after 10 patients of the projected 20 Phase 2a patients completed treatment (100% cured infection at End of Treatment (10 of 10). In the Phase 2b trial segment, 32 patients with CDI were enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours, in each case, for 10 days and followed for 28 ± 2 days following the end of treatment for recurrence of CDI. The two treatments were identical in appearance, dosing times, and number of capsules administered to maintain the blind. In this Phase 2b trial segment, 15 out of 16 (94%) patients in Phase 2b in the Per Protocol Population experienced Clinical Cure (CC) and all 15 of 15 (100%) remained free of C. difficile infection (CDI) recurrence through one month after EOT. When Phase 2b results are combined with Phase 2a results, the Clinical Cure rate in patients with CDI was 96% (25 out of 26 patients), based on 10 out of 10 patients (100%) in Phase 2a in the Modified Intent to Treat Population, plus 15 out of 16 (94%) patients in Phase 2b in the Per Protocol Population, who experienced Clinical Cure during treatment with ibezapolstat. Notably, in the combined Phase 2 trial, 100% (25 of 25) ibezapolstat-treated patients) who had Clinical Cure at EOT) (End of Treatment) remained cured through one month after EOT, as compared to 86% (12 of 14) for the vancomycin patient group. Ibezapolstat was well-tolerated, with no serious adverse events assessed by the blinded investigator to be drug- related. The Company is confident that based on the pooled Phase 2 ibezapolstat Clinical Cure rate of 96%, Sustained Clinical Cure Rate of 100% and the historical vancomycin Clinical Cure Rate range of 70% to 92% and a Sustained Clinical Cure historical range of 42% to 74%, we will demonstrate non-inferiority of ibezapolstat to vancomycin in Phase 3 trials, in accordance with the applicable FDA Guidance for Industry (October 2022), with favorable differentiation in both Clinical Cure and Sustained Clinical Cure. In the Phase 2 clinical trial (both trial segments), the Company also evaluated pharmacokinetics (PK) and microbiome changes and test for anti-recurrence microbiome properties, including the change from baseline in alpha diversity and bacterial abundance, especially overgrowth of healthy gut microbiota Actinobacteria and Firmicute phylum species during and after therapy. Phase 2a data demonstrated complete eradication of colonic C. difficile by day three of treatment with ibezapolstat as well as the observed overgrowth of healthy gut microbiota, Actinobacteria and Firmicute phyla species, during and after therapy. Very importantly, emerging data show an increased concentration of secondary bile acids during and following ibezapolstat therapy which is known to correlate with colonization resistance against C. difficile. A decrease in primary bile acids and the favorable increase in the ratio of secondary-to-primary bile acids suggest that ibezapolstat may reduce the likelihood of CDI recurrence when compared to vancomycin. The company also reported positive extended clinical cure (ECC) data for ibezapolstat (IBZ), its lead antibiotic candidate, from the Company's recently completed Phase 2b clinical trial in patients with CDI. This exploratory endpoint showed that 5 of 5 IBZ patients followed for up to three months following Clinical Cure experienced no recurrence of infection. Furthermore, ibezapolstat-treated patients showed lower concentrations of fecal primary bile acids, and higher beneficial ratio of secondary to primary bile acids than vancomycin-treated patients. About Ibezapolstat Ibezapolstat is the Company's lead antibiotic candidate planning to advance to international Phase 3 clinical trials to treat patients with C. difficile infection. Ibezapolstat is a novel, orally administered antibiotic, being developed as a Gram-Positive Selective Spectrum (GPSS®) antibacterial. It is the first of a new class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Ibezapolstat's unique spectrum of activity, which includes C. difficile but spares other Firmicutes and the important Actinobacteria phyla, appears to contribute to the maintenance of a healthy gut microbiome. In June 2018, ibezapolstat was designated by the U.S. Food and Drug Administration (FDA) as a Qualified Infectious Disease Product (QIDP) for the treatment of patients with CDI and will be eligible to benefit from the incentives for the development of new antibiotics established under the Generating New Antibiotic Incentives Now (GAIN) Act. In 2019, FDA granted "Fast Track" designation to ibezapolstat for the treatment of patients with CDI. The CDC has designated C. difficile as an urgent threat highlighting the need for new antibiotics to treat CDI. About Clostridioides difficile Infection According to the 2017 Update (published February 2018) of the Clinical Practice Guidelines for C. difficile Infection by the Infectious Diseases Society of America (IDSA) and Society or Healthcare Epidemiology of America (SHEA), CDI remains a significant medical problem in hospitals, in long-term care facilities and in the community. C. difficile is one of the most common causes of health care- associated infections in U.S. hospitals (Lessa, 2015, NEJM). Recent estimates suggest C. difficile approaches 500,000 infections annually in the U.S. and is associated with approximately 20,000 deaths annually. (Guh, 2020, NEJM. Based on internal estimates, the recurrence rate for the antibiotics currently used to treat CDI is between 20% and 40% among approximately 150,000 patients treated. We believe the annual incidence of CDI in the U.S. approaches 600,000 infections and a mortality rate of approximately 9.3%. About the Microbiome in C. difficile Infection and Bile Acid Metabolism C. difficile can be a normal component of the healthy gut microbiome, but when the microbiome is thrown out of balance, the C. difficile can thrive and cause an infection. After colonization with C. difficile, the organism produces and releases the main virulence factors, the two large clostridial toxins A (TcdA) and B (TcdB). (Kachrimanidou, Microorganisms 2020.) TcdA and TcdB are exotoxins that bind to human intestinal epithelial cells and are responsible for inflammation, fluid and mucous secretion, as well as damage to the intestinal mucosa. Bile acids perform many functional roles in the GI tract, with one of the most important being maintenance of a healthy microbiome by inhibiting C. difficile growth. Primary bile acids, which are secreted by the liver into the intestines, promote germination of C. difficile spores and thereby increase the risk of recurrent CDI after successful treatment of an initial episode. On the other hand, secondary bile acids, which are produced by normal gut microbiota through metabolism of primary bile acids, do not induce C. difficile sporulation and therefore protect against recurrent disease. Since ibezapolstat treatment leads to minimal disruption of the gut microbiome, bacterial production of secondary bile acids continues which may contribute to an anti-recurrence effect. Beneficial effects of bile acids include a decrease in primary bile acids and an increase in secondary bile acids in patients with CDI, which was observed in the Company's Ph2a trial results and previously reported (Garey, CID, 2022). In the Ph2b trial, ibezapolstat-treated patients showed lower concentrations of fecal primary bile acids, and higher beneficial ratio of secondary to primary bile acids than vancomycin-treated patients. Forward-Looking Statements Any statements in this press release about our future expectations, plans and prospects, including statements regarding our strategy, future operations, prospects, plans and objectives, and other statements containing the words "believes," "anticipates," "plans," "expects," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: whether ibezapolstat will benefit from the QIDP designation; whether ibezapolstat will advance through the clinical trial process on a timely basis; whether the results of the clinical trials of ibezapolstat will warrant the submission of applications for marketing approval, and if so, whether ibezapolstat will receive approval from the FDA or equivalent foreign regulatory agencies where approval is sought; whether, if ibezapolstat obtains approval, it will be successfully distributed and marketed; and other risks and uncertainties described in the Company's annual report filed with the Securities and Exchange Commission on Form 10-K for the year ended December 31, 2024, and in the Company's subsequent filings with the Securities and Exchange Commission. Such forward- looking statements speak only as of the date of this press release, and Acurx disclaims any intent or obligation to update these forward-looking statements to reflect events or circumstances after the date of such statements, except as may be required by law. Investor Contact: Acurx Pharmaceuticals, Inc., David P. Luci, President & CEO Tel: 917-533-1469, Email: [email protected] SOURCE Acurx Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED