Lipophosphonoxins - Novel broad-spectrum antimicrobial agents
Dr Dominik Rejman, Institute of Organic Chemistry and Biochemistry (IOCB); Dr Duy Dinh Do Pha, Institute of Organic Chemistry and Biochemistry CAS; Dr Libor Krásný, Institute of Microbiology CAS; Prof. Milan Kolář, University of Palacký Olomouc; Dr Gabriela Mikušová, Institute of Organic Chemistry and Biochemistry CAS
Growing antimicrobial resistance to currently available antibiotics poses a major threat to public health worldwide and presents an urgent need for novel effective antimicrobial compounds. Here, we present a novel class of antimicrobial compounds with low potential for resistance development.
The compounds show significant inhibitory and bactericidal activities against a broad spectrum of clinically relevant gram-positive and gram-negative pathogens, including resistant strains. Our compounds selectively target the bacterial membrane. Their action is rapid, allowing the pathogens limited time to develop resistance mechanisms. Our compounds do not damage eukaryotic cell membranes (at therapeutically relevant concentrations) and show no in vivo toxicity up to a dose of 2000 mg/kg (when administered orally to mice). They are well tolerated when applied on the skin or into the eye. As the compounds do not absorb through the gastrointestinal tract, they are intended for topical treatment. Recently, we have performed an in vivo experiment showing the ability of the second generation LPPO, topically applied using a carrier, to block S. aureus infection in mice. Currently, we are developing a newer generation of LPPO with further improved antibacterial properties.
The market size for drugs to treat bacterial infections was estimated at ca. 7.5 billion USD (2020 prediction, includes data from the US, India, Japan, and 5 major EU markets). Source: Global Data
Lead optimization, preclinical (in vitro and in vivo evidence)
EP 2 527 351 B1, 11.12.2013, 2013.
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2) Lipophosphonoxins: new modular molecular structures with significant antibacterial properties. Rejman D, Rabatinová A, Pombinho AR, Kovačková S, Pohl R, Zborníková E, Kolář M, Bogdanová K, Nyč O, Sanderová H, Látal T, Bartůněk P, Krásný L. J Med Chem. 2011 Nov 24;54(22):7884-98. doi: 10.1021/jm2009343. Epub 2011 Nov 1.