Structure–Activity Relationship of Amino Acid
Tunable Lipidated Norspermidine Conjugates: Disrupting Biofilms with
Potent Activity against Bacterial Persisters
- Publication date
- Publisher
Abstract
The emergence of bacterial resistance
and biofilm associated infections
has created a challenging situation in global health. In this present
state of affairs where conventional antibiotics are falling short
of being able to provide a solution to these problems, development
of novel antibacterial compounds possessing the twin prowess of antibacterial
and antibiofilm efficacy is imperative. Herein, we report a library
of amino acid tunable lipidated norspermidine conjugates that were
prepared by conjugating both amino acids and fatty acids with the
amine functionalities of norspermidine through amide bond formation.
These lipidated conjugates displayed potent antibacterial activity
against various planktonic Gram-positive and Gram-negative bacteria
including drug-resistant superbugs such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and β-lactam-resistant Klebsiella pneumoniae. This class of nontoxic and
fast-acting antibacterial molecules (capable of killing bacteria within
15 min) did not allow bacteria to develop resistance against them
after several passages. Most importantly, an optimized compound in
the series was also capable of killing metabolically inactive persisters
and stationary phase bacteria. Additionally, this compound was capable
of disrupting the preformed biofilms of S. aureus and E. coli. Therefore, this class
of antibacterial conjugates have potential in tackling the challenging
situation posed by both bacterial resistance as well as drug tolerance
due to biofilm formation