Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs)
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Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs). / Couturier, Cédric; Ronzon, Quentin; Lattanzi, Giulia; Lingard, Iain; Coyne, Sebastien; Cazals, Veronique; Dubarry, Nelly; Yvon, Stephane; Leroi-Geissler, Corinne; Gracia, Obdulia Rabal; Teague, Joanne; Sordello, Sylvie; Corbett, David; Bauch, Caroline; Monlong, Chantal; Payne, Lloyd; Taillier, Thomas; Fuchs, Hazel; Broenstrup, Mark; Harrison, Peter H.; Moynié, Lucile; Lakshminarayanan, Abirami; Gianga, Tiberiu Marius; Hussain, Rohanah; Naismith, James H.; Mourez, Michael; Bacqué, Eric; Björkling, Fredrik; Sabuco, Jean Francois; Franzyk, Henrik.
In: European Journal of Medicinal Chemistry, Vol. 265, 116097, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs)
AU - Couturier, Cédric
AU - Ronzon, Quentin
AU - Lattanzi, Giulia
AU - Lingard, Iain
AU - Coyne, Sebastien
AU - Cazals, Veronique
AU - Dubarry, Nelly
AU - Yvon, Stephane
AU - Leroi-Geissler, Corinne
AU - Gracia, Obdulia Rabal
AU - Teague, Joanne
AU - Sordello, Sylvie
AU - Corbett, David
AU - Bauch, Caroline
AU - Monlong, Chantal
AU - Payne, Lloyd
AU - Taillier, Thomas
AU - Fuchs, Hazel
AU - Broenstrup, Mark
AU - Harrison, Peter H.
AU - Moynié, Lucile
AU - Lakshminarayanan, Abirami
AU - Gianga, Tiberiu Marius
AU - Hussain, Rohanah
AU - Naismith, James H.
AU - Mourez, Michael
AU - Bacqué, Eric
AU - Björkling, Fredrik
AU - Sabuco, Jean Francois
AU - Franzyk, Henrik
N1 - Publisher Copyright: © 2023 Elsevier Masson SAS
PY - 2024
Y1 - 2024
N2 - Tridecaptins comprise a class of linear cationic lipopeptides with an N-terminal fatty acyl moiety. These 13-mer antimicrobial peptides consist of a combination of D- and L-amino acids, conferring increased proteolytic stability. Intriguingly, they are biosynthesized by non-ribosomal peptide synthetases in the same bacterial species that also produce the cyclic polymyxins displaying similar fatty acid tails. Previously, the des-acyl analog of TriA1 (termed H-TriA1) was found to possess very weak antibacterial activity, albeit it potentiated the effect of several antibiotics. In the present study, two series of des-acyl tridecaptins were explored with the aim of improving the direct antibacterial effect. At the same time, overall physico-chemical properties were modulated by amino acid substitution(s) to diminish the risk of undesired levels of hemolysis and to avoid an impairment of mammalian cell viability, since these properties are typically associated with highly hydrophobic cationic peptides. Microbiology and biophysics tools were used to determine bacterial uptake, while circular dichroism and isothermal calorimetry were used to probe the mode of action. Several analogs had improved antibacterial activity (as compared to that of H-TriA1) against Enterobacteriaceae. Optimization enabled identification of the lead compound 29 that showed a good ADMET profile as well as in vivo efficacy in a variety of mouse models of infection.
AB - Tridecaptins comprise a class of linear cationic lipopeptides with an N-terminal fatty acyl moiety. These 13-mer antimicrobial peptides consist of a combination of D- and L-amino acids, conferring increased proteolytic stability. Intriguingly, they are biosynthesized by non-ribosomal peptide synthetases in the same bacterial species that also produce the cyclic polymyxins displaying similar fatty acid tails. Previously, the des-acyl analog of TriA1 (termed H-TriA1) was found to possess very weak antibacterial activity, albeit it potentiated the effect of several antibiotics. In the present study, two series of des-acyl tridecaptins were explored with the aim of improving the direct antibacterial effect. At the same time, overall physico-chemical properties were modulated by amino acid substitution(s) to diminish the risk of undesired levels of hemolysis and to avoid an impairment of mammalian cell viability, since these properties are typically associated with highly hydrophobic cationic peptides. Microbiology and biophysics tools were used to determine bacterial uptake, while circular dichroism and isothermal calorimetry were used to probe the mode of action. Several analogs had improved antibacterial activity (as compared to that of H-TriA1) against Enterobacteriaceae. Optimization enabled identification of the lead compound 29 that showed a good ADMET profile as well as in vivo efficacy in a variety of mouse models of infection.
KW - Antibiotic
KW - Antimicrobial peptides
KW - Gram-negative bacteria
KW - Solid-phase peptide synthesis
KW - Structure-activity relationships
KW - tridecaptins
U2 - 10.1016/j.ejmech.2023.116097
DO - 10.1016/j.ejmech.2023.116097
M3 - Journal article
C2 - 38157595
AN - SCOPUS:85181056903
VL - 265
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 116097
ER -
ID: 380203118