Novel bacterial Type II topoisomerase inhibitors for the treatment of bacterial infections
Multiple novel series of small molecule inhibitors of DNA gyrase and topoisomerase IV, including a lead anti-MRSA molecule with in vivo efficacy and a favorable in vitro safety profile. The technology offers potential options for Gram-positive pathogens (including MRSA, VRE, and Streptococcus pneumoniae), Gram-negative bacteria such as Neisseria gonorrhoeae and Acinetobacter baumannii, and mycobacteria (including Mycobacterium tuberculosis and non-tuberculous mycobacteria).
Antibiotic-resistant infections threaten large numbers of patients: the CDC conservatively estimates ~2 million such infections and 23,000 deaths annually in the United States alone. Globally, experts attributed 1.3 million deaths to resistant bacterial infections in 2019, with six pathogens accounting for >70% of the total (Escherichia coli, Staphylococcus aureus, S. pneumoniae, Klebsiella pneumoniae, A. baumannii, and Pseudomonas aeruginosa). Drug-resistant gonorrhea has increased dramatically in recent years, leaving injectable ceftriaxone as the only reliably active option. Tuberculosis killed ~1.5 million people worldwide in 2020, and there remains a substantial opportunity for new combination therapies with better tolerability and shorter treatment duration. Without significant innovation, the rise in antibiotic-resistant infections may undermine the very practice of modern medicine. Against this backdrop, new and differentiated antibacterial agents lacking cross-resistance to existing therapies are badly needed.
Antibacterial research in the laboratory of Dr. Mark Mitton-Fry at The Ohio State University College of Pharmacy has led to the discovery of Novel Bacterial Topoisomerase Inhibitors (NBTIs) with activity against key pathogens driving substantial morbidity and mortality in the United States and across the world. Rational design focused on physicochemical properties such as basicity and lipophilicity has reduced safety concerns associated with many early NBTIs. The lab emphasizes synthetic simplicity and efficiency. It collaborates widely at Ohio State and with external experts, and has diverse internal capabilities including biochemical pharmacology, microbiology, computational chemistry, and structural biology. The Mitton-Fry lab has identified molecules with in vivo efficacy in multiple models of MRSA infection and tuberculosis. Promise against other pathogens, including N. gonorrhoeae, is supported by in vitro studies conducted externally. Additional applications of this technology include non-tuberculous mycobacterial and other infections of particular relevance to individuals living with cystic fibrosis.
· Skin and skin structure infections
· Community acquired bacterial pneumonia
· Ability to target multiple bacterial pathogens
· Potential for oral and intravenous formulations
· Absence of cross-resistance to currently marketed antibiotics
· Low potential for resistance emergence
· Rationally designed improvements in cardiovascular safety
Issued in US (11,352,349) and pending in AU, CA, EU, and HK
Prof. Mitton-Fry has demonstrated expertise in antibacterial drug discovery and development. Collaborative opportunities exploiting new targets and/or new chemotypes are welcome.