Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy
Authors
Kokot, MajaWeiss, Matjaž
Zdovc, Irena
Šenerović, Lidija
Radakovic, Natasa
Anderluh, Marko
Minovski, Nikola
Hrast, Martina
Article (Published version)
Metadata
Show full item recordAbstract
Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh infection model of MRSA infection.
Keywords:
Antibacterials / DNA gyrase / hERG inhibition / In vivo efficacy / MRSA / NBTIs / Topoisomerase IVSource:
European Journal of Medicinal Chemistry, 2023, 250, 115160-Funding / projects:
- This work was supported by the Slovenian Research Agency (Grants P1-0017 and P1-0208, the young researcher’s program numbers 39010 and 50503) and by Proof of Concept project NICKI of the National Institute of Chemistry, and University of Ljubljana Innovation Fund.
URI
https://www.sciencedirect.com/science/article/pii/S0223523423000752https://imagine.imgge.bg.ac.rs/handle/123456789/1779
Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Kokot, Maja AU - Weiss, Matjaž AU - Zdovc, Irena AU - Šenerović, Lidija AU - Radakovic, Natasa AU - Anderluh, Marko AU - Minovski, Nikola AU - Hrast, Martina PY - 2023 UR - https://www.sciencedirect.com/science/article/pii/S0223523423000752 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1779 AB - Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh infection model of MRSA infection. T2 - European Journal of Medicinal Chemistry T2 - European Journal of Medicinal ChemistryEuropean Journal of Medicinal Chemistry T1 - Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy SP - 115160 VL - 250 DO - 10.1016/j.ejmech.2023.115160 ER -
@article{ author = "Kokot, Maja and Weiss, Matjaž and Zdovc, Irena and Šenerović, Lidija and Radakovic, Natasa and Anderluh, Marko and Minovski, Nikola and Hrast, Martina", year = "2023", abstract = "Novel bacterial topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh infection model of MRSA infection.", journal = "European Journal of Medicinal Chemistry, European Journal of Medicinal ChemistryEuropean Journal of Medicinal Chemistry", title = "Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy", pages = "115160", volume = "250", doi = "10.1016/j.ejmech.2023.115160" }
Kokot, M., Weiss, M., Zdovc, I., Šenerović, L., Radakovic, N., Anderluh, M., Minovski, N.,& Hrast, M.. (2023). Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy. in European Journal of Medicinal Chemistry, 250, 115160. https://doi.org/10.1016/j.ejmech.2023.115160
Kokot M, Weiss M, Zdovc I, Šenerović L, Radakovic N, Anderluh M, Minovski N, Hrast M. Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy. in European Journal of Medicinal Chemistry. 2023;250:115160. doi:10.1016/j.ejmech.2023.115160 .
Kokot, Maja, Weiss, Matjaž, Zdovc, Irena, Šenerović, Lidija, Radakovic, Natasa, Anderluh, Marko, Minovski, Nikola, Hrast, Martina, "Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy" in European Journal of Medicinal Chemistry, 250 (2023):115160, https://doi.org/10.1016/j.ejmech.2023.115160 . .