Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy
Аутори
Kokot, MajaWeiss, Matjaž
Zdovc, Irena
Šenerović, Lidija
Radakovic, Natasa
Anderluh, Marko
Minovski, Nikola
Hrast, Martina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Antibacterials / DNA gyrase / hERG inhibition / In vivo efficacy / MRSA / NBTIs / Topoisomerase IVИзвор:
European Journal of Medicinal Chemistry, 2023, 250, 115160-Финансирање / пројекти:
- 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
Институција/група
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 . .