Gepotidacin (GSK2140944)

Gepotidacin (GSK2140944) is a novel, bactericidal, oral, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes^[1]. Gepotidacin inhibits both DNA gyrase and topoisomerase IV. More specifically, Gepotidacin binds to the GyrA subunit of DNA gyrase and to the ParC subunit of topoisomerase IV. With its novel chemical scaffold, Gepotidacin can form a ternary complex with DNA and two GyrA or ParC subunits^[2].

In vitro, Gepotidacin (10^-4, 10^-3, 10^-2, 10^-1, 10, 10¹, 10², 10³mg/L) treatment of THP-1 monocytes for 24 h effectively reduced the intracellular bacterial burden, regardless of the resistance phenotype of the strain. Gepotidacin demonstrated a high rate of cellular uptake and efflux. Moreover, the activity of Gepotidacin developed in a concentration-dependent manner^[3]. Additionally, Gepotidacin has shown potent bactericidal effects against a diverse range of pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and extended-spectrum β-lactamase-producing Escherichia coli ^[4-5].

In vivo, Gepotidacin doses of 1.56 to 400mg/kg of body weight every 6h subcutaneous (s.c.) injections were utilized for mice. Gepotidacin displayed activity against MRSA^[6]. The pharmacokinetic-pharmacodynamic (PK-PD) parameters of Gepotidacin against S. aureus and S. pneumoniae were characterized, using neutropenic mouse models of thigh and lung infection. The result implied that Gepotidacin activity was concentration-dependent^[7].

Reference:
[1] Watkins RR, Thapaliya D, Lemonovich TL, Bonomo RA. Gepotidacin: a novel, oral, 'first-in-class' triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea. J Antimicrob Chemother. 2023;78(5):1137-1142.
[2] Ruggieri F, Compagne N, Antraygues K, Eveque M, Flipo M, Willand N. Antibiotics with novel mode of action as new weapons to fight antimicrobial resistance. Eur J Med Chem. 2023;256:115413.
[3] Peyrusson F, Tulkens PM, Van Bambeke F. Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin against Staphylococcus aureus Isolates with Different Resistance Phenotypes in Models of Cultured Phagocytic Cells. Antimicrob Agents Chemother. 2018;62(4):e02245-17.
[4] Biedenbach DJ, Bouchillon SK, Hackel M, et al. In Vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, against a Broad Spectrum of Bacterial Pathogens. Antimicrob Agents Chemother. 2016;60(3):1918-1923.
[5] Flamm RK, Farrell DJ, Rhomberg PR, Scangarella-Oman NE, Sader HS. Gepotidacin (GSK2140944) In Vitro Activity against Gram-Positive and Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017;61(7):e00468-17.
[6] So W, Crandon JL, Nicolau DP. Pharmacodynamic Profile of GSK2140944 against Methicillin-Resistant Staphylococcus aureus in a Murine Lung Infection Model. Antimicrob Agents Chemother. 2015;59(8):4956-4961.
[7] Bulik CC, Okusanya ÓO, Lakota EA, et al. Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models. Antimicrob Agents Chemother. 2017;61(2):e00115-16.

Gepotidacin (GSK2140944)是一种新型、杀菌性口服三氮杂萘类抗生素，可通过阻断两种必需的拓扑异构酶来抑制细菌DNA复制^[1]。Gepotidacin可抑制DNA旋转酶和拓扑异构酶IV，更具体地说，它可与DNA旋转酶的GyrA亚基和拓扑异构酶IV的ParC亚基结合。由于其新颖的化学骨架，Gepotidacin可与DNA及两个GyrA或ParC亚基形成三元复合物 ^[2]。

在体外，Gepotidacin（10⁻⁴、10⁻³、10⁻²、10⁻¹、10、10¹、10²、10³mg/L）处理THP-1单核细胞24小时，能有效减少细胞内的细菌负荷，且这一效果不受菌株耐药表型的影响。Gepotidacin表现出较高的细胞摄取和排出速率。此外，Gepotidacin的活性呈浓度依赖性发展^[3]。另外，Gepotidacin已显示出对多种病原体具有强大的杀菌效果，包括耐甲氧西林金黄色葡萄球菌（MRSA）、耐青霉素肺炎链球菌以及产超广谱β-内酰胺酶的大肠杆菌^[4-5]。

在体内，Gepotidacin以1.56至400mg/kg体重的剂量，每6小时皮下注射一次，用于小鼠体内实验。Gepotidacin对MRSA表现出抗菌活性^[6]。通过中性粒细胞减少型小鼠的大腿感染和肺部感染模型，研究了Gepotidacin对金黄色葡萄球菌和肺炎链球菌的药代动力学-药效学（PK-PD）参数。结果表明，Gepotidacin的抗菌活性呈浓度依赖性^[7]。