Susceptibility and resistance of Gram-negative bacteria to a novel antimicrobial agent TGV-49

Victor Tetz¹Kristina Kardava¹Maria Vecherkovskaya¹Semen A Leyn²Marinela Elane²Andrei Osterman²George Tetz^1,3*

• ¹Department of Microbiology, Virology and Immunology, Human Microbiology Institute, New York, St.Petersburg, United States
• ²Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States
• ³Tetz Laboratories, New York, United States

Introduction: Antimicrobial resistance remains a major global public health challenge that necessitates novel drugs with a low resistance rate. Methods: Herein, we evaluate TGV-49, a novel broad-spectrum antimicrobial agent, against multidrug-resistant Gram-negative bacteria, including ESKAPE pathogens (Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and pathogens from agriculture that infect humans (Ralstonia solanacearum and Aeromonas hydrophila). Results: TGV-49 was highly effective in overcoming resistance to conventional antibiotics. The experimental evolution of A. baumannii using a morbidostat revealed minimal development of resistance. Conclusion: Our findings suggest TGV-49 as a potential alternative for combating MDR infections in clinical and agricultural settings. Statement Antimicrobial resistance among Gram-negative pathogens poses a critical global health challenge, with limited treatment options due to antibiotic resistance. The spread of microorganisms in healthcare settings with antibiotic resistance acquired from agricultural and aquacultural environments has exacerbated this challenge. This study aims to evaluate TGV-49, a novel antimicrobial agent, for its activity against different drug-resistant Gram-negative bacteria, including ESKAPE pathogens and those from environmental sources. TGV-49 revealed high activity against pathogens of various sources, including healthcare settings, agricultural, and aquatic pathogens, with low minimum inhibitory concentration (MIC) values across susceptible strains and strains resistant to existing antibiotics, including last-resort ones. Furthermore, this study investigates the evolution of resistance in Acinetobacter baumannii toward TGV-49 using a morbidostat, whole-genome sequencing-based experimental evolution system. Only minimal resistance emerged in one of the six tested populations, indicating a lower tendency to promote rapid resistance evolution than many current antibiotics, which often become ineffective due to resistance. These findings support TGV-49 as a candidate for future development as an alternative for combating MDR infections.