Novel Broad-Spectrum Antimicrobial Agents to overcome bacterial resistance
Growing antimicrobial resistance poses a significant threat to public health worldwide. A recent review of the antibiotic pipeline by the World Health Organization (WHO, 17th January 2020) states that the majority of the current drug candidates may have limited benefits compared to already marketed drugs. Innovative solutions are urgently needed.
Lipophosphonoxins (LPPOs) are novel broad-spectrum antimicrobials with a rapid mechanism of action and low propensity for resistance development. LPPOs selectively target the bacterial membrane of a broad spectrum of clinically relevant Gram-positive and Gram-negative pathogens, including resistant strains (Fig. 1), without damaging eukaryotic cell membranes. As the compounds do not absorb through the gastrointestinal tract, they are intended for topical treatment (for example, in skin infections – Fig. 2).
Antibiotic-resistant infections of the skin and soft tissues are common and may complicate wound healing, e.g., in patients with diabetic ulcers or burn injuries. To address this problem, nanofibrous material with controlled release of LPPOs is currently being developed in collaboration with Charles University in Prague and the Technical University of Liberec.
Figure 1. A schematic illustration of LPPO action and MIC values of selected LPPO against several clinically relevant bacterial strains including resistant ones.
Figure 2. Efficacy of LPPOs against skin infection caused by S. aureus in a mouse model. The photos show uninfected (Control) and Staphylococcus aureus-infected wounds that were either untreated (S.aureus) or NANO-LPPO treated (S.aureus+LPPO). The graph shows the number of remaining bacteria as determined by qPCR.
This project is offered for licensing/collaboration/co-development.
The project is in the preclinical/lead optimization phase.
EP 2 527 351 B1, 11.12.2013, 2013; WO2017186200A1; Czech patent application for the latest generation of compounds – Dec 2019 (PV 2019-769), nanoLPPO
1) Seydlová G(1), Pohl R(2), Zborníková E(2)(3), Ehn M(2), Šimák O(2), Panova N(4), Kolář M(5), Bogdanová K(5), Večeřová R(5), Fišer R(1), Šanderová H(4), Vítovská D(4), Sudzinová P(1)(4), Pospíšil J(1)(4), Benada O(4), Křížek T(3), Sedlák D(6), Bartůněk P(6), Krásný L(4), Rejman D(2). Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents. J Med Chem. 2017 Jul 27;60(14):6098-6118. doi: 10.1021/acs.jmedchem.7b00355. Epub 2017 Jul 12.
2) Rejman D(1), Rabatinová A, Pombinho AR, Kovačková S, Pohl R, Zborníková E, Kolář M, Bogdanová K, Nyč O, Sanderová H, Látal T, Bartůněk P, Krásný L. Lipophosphonoxins: new modular molecular structures with significant antibacterial properties. J Med Chem. 2011 Nov 24;54(22):7884-98. doi: 10.1021/jm2009343. Epub 2011 Nov 1.
