Resistance to aminoglycoside antibiotics is a serious problem,typically arising from inactivating enzymes, reduced uptake, or increasedefflux in the important pathogens for which they are used as treatment.Conjugating aminoglycosides to proline-rich antimicrobial peptides(PrAMPs), which also target ribosomes and have a distinct bacterialuptake mechanism, might mutually benefit their individual activities.To this aim we have developed a strategy for noninvasively modifyingtobramycin to link it to a Cys residue and through this covalentlylink it to a Cys-modified PrAMP by formation of a disulfide bond.Reduction of this bridge in the bacterial cytosol should release theindividual antimicrobial moieties. We found that the conjugation oftobramycin to the well-characterized N-terminal PrAMP fragment Bac7(1-35)resulted in a potent antimicrobial capable of inactivating not onlytobramycin-resistant bacterial strains but also those less susceptibleto the PrAMP. To a certain extent, this activity also extends to theshorter and otherwise poorly active fragment Bac7(1-15). Althoughthe mechanism that allows the conjugate to act when its individualcomponents do not is as yet unclear, results are very promising andsuggest this may be a way of resensitizing pathogens that have developedresistance to the antibiotic.

Designing New Hybrid Antibiotics: Proline-Rich Antimicrobial Peptides Conjugated to the Aminoglycoside Tobramycin

Gambato, Stefano;Bellotto, Ottavia;Mardirossian, Mario;Di Stasi, Adriana;Gennaro, Renato;Pacor, Sabrina;Berti, Federico;Scocchi, Marco
;
Tossi, Alessandro
2023-01-01

Abstract

Resistance to aminoglycoside antibiotics is a serious problem,typically arising from inactivating enzymes, reduced uptake, or increasedefflux in the important pathogens for which they are used as treatment.Conjugating aminoglycosides to proline-rich antimicrobial peptides(PrAMPs), which also target ribosomes and have a distinct bacterialuptake mechanism, might mutually benefit their individual activities.To this aim we have developed a strategy for noninvasively modifyingtobramycin to link it to a Cys residue and through this covalentlylink it to a Cys-modified PrAMP by formation of a disulfide bond.Reduction of this bridge in the bacterial cytosol should release theindividual antimicrobial moieties. We found that the conjugation oftobramycin to the well-characterized N-terminal PrAMP fragment Bac7(1-35)resulted in a potent antimicrobial capable of inactivating not onlytobramycin-resistant bacterial strains but also those less susceptibleto the PrAMP. To a certain extent, this activity also extends to theshorter and otherwise poorly active fragment Bac7(1-15). Althoughthe mechanism that allows the conjugate to act when its individualcomponents do not is as yet unclear, results are very promising andsuggest this may be a way of resensitizing pathogens that have developedresistance to the antibiotic.
2023
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https://pubs.acs.org/doi/10.1021/acs.bioconjchem.2c00467
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/3052521
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