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Novel antibacterial compound lipophosphonoxins: design, synthesis, evaluation, and applications

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    0567291 - ÚOCHB 2023 RIV CZ eng A - Abstract
    Do Pham, Duy Dinh - Mojr, Viktor - Petrová, Magdalena - Krásný, Libor - Kolář, M. - Fišer, R. - Rejman, Dominik
    Novel antibacterial compound lipophosphonoxins: design, synthesis, evaluation, and applications.
    Czech Chemical Society Symposium Series. Roč. 20, č. 6 (2022), s. 347-347. ISSN 2336-7202.
    [Annual meeting of the National Institute of Virology and Bacteriology (NIVB) /1./. 30.11.2022-02.12.2022, Kutná Hora]
    R&D Projects: GA MŠk(CZ) LX22NPO5103
    Institutional support: RVO:61388963 ; RVO:61388971
    Keywords : lipophosphonoxins * antibacterial * LPPO
    OECD category: Organic chemistry

    Most of the antibiotics in use today are derivatives of natural products of actinomycetes and fungi.1Medicinal chemistry has played a key role in modifying natural products to optimize their pharmacological properties, while minimizing toxicity.2Nevertheless, bacterial diseases resistant to currently available drugs already cause at least 700,000 deaths globally a year, including 230,000 deaths from multidrug-resistant tuberculosis, a figure that could increase to 10 million deaths globally per year by 2050 under the most alarming scenario if no action is taken. LPPOs are small amphiphilic molecules bearing positive charge(s). LPPO consist of four modules: (i) a nucleoside module NM, (ii) a polar module PM, (iii) a hydrophobic module HM (lipophilic alkyl chain), and (iv) a phosphonate connector module CM that holds together modules (i)-(iii) (Fig. 1). This first-generation LPPO (LPPO I)1demonstrated excellent bactericidal activity against various Gram-positive species, including multi-resistant strains such as vancomycin-resistant enterococci or methicillin-resistant Staphylococcus aureus. We have shown that at their bactericidal concentrations, LPPO act via disruption of the cytoplasmic membrane. By redesigning the iminosugar module so that it bears more positive charges, we developed the second generation of LPPO (LPPO II) with increased efficacy against Gram-positive species and an extended antibacterial activity range that now also includes serious Gram-negative pathogens.2LPPO II cause serious damage to the bacterial cell membrane, efflux of the bacterial cytosol and cell disintegration. Furthermore, LPPO II were shown to be well tolerated by live mice when administered orally and to cause no skin irritation in rabbits.Importantly, using several of the most potent LPPO I and LPPO II we failed to select resistantstrains ofBacillus subtilis, Enterococcus faecalis, Streptococcus agalactiaeor Pseudomonas aeruginosa, while strains resistant to known conventional antibiotics (rifampicin and ciprofloxacin) readily emerged in control experiments. Recently, LPPO II were evaluated as additives in polymethylmethacrylate (PMMA) bone cements, preventing infections3and as an antibacterial component of polycaprolactone electrospun nanofiber dressing capable of reducing S. aureusinduced wound infection in mice.4Here we present the synthesis and evaluation of novel antibacterial compounds termed LEGO-LPPOs. LEGO-LPPOs are loosely based on LPPOs but with a dramatically altered modular architecture of the molecule. LEGO-LPPOs consist of a central linker module LMwith two attached connector modules CM on either side. The connector modules are then decorated with polar PM and hydrophobic modules HM. We performed an extensive structure-activity relationship study by varying the length of the linker and hydrophobic modules, synthesizing >80 compounds. We identified the best compounds active against both Gram-negative and -positive species including multiresistant strains and persisters. LEGO-LPPOs act by first depleting the membrane potential and then creating pores in the cytoplasmic membrane. Importantly, their efficacy is not affected by the presence of serum albumins. Low cytotoxicity and low propensity for resistance development demonstrate their potential for further studies and possible therapeutic use.
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    L-01 UOCHB_Rejman.pdf27202.7 KBPublisher’s postprintopen-access
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