Octadecyl 3-(3, 5-di-tert-butyl-4-hydroxyphenyl) propanoate nanosponges: enhanced antibacterial and antibiofilm activity against multidrug-resistant Klebsiella pneumoniae with synergistic ceftriaxone combination.

Global public health is seriously threatened by the rising incidence of multidrug-resistant (MDR) Klebsiella pneumoniae, underscoring the critical need for innovative antimicrobial approaches. Herein, the antibacterial and antibiofilm activities of octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propanoate (ODHP) and its nanosponge formulation (ODHP-NS) were evaluated against clinical MDR K. pneumoniae isolates, and the potential synergistic interaction between ODHP-NS and ceftriaxone was investigated using the checkerboard assay and further confirmed by time-kill kinetics. Results showed that ODHP-NS exhibited enhanced antibacterial activity compared to ODHP, with lower MIC50 and MIC90 values (32 vs. 96 µg/mL and 128 vs. 256 µg/mL, respectively), indicating improved efficacy following nanosponge formulation. Both ODHP and ODHP-NS demonstrated significant inhibition of biofilm formation at sub-inhibitory concentrations (1/2 and 1/4 MIC), with ODHP-NS showing significantly higher antibiofilm activity (p < 0.0001). Fractional inhibitory concentration index (FICI) values indicated synergistic to additive effects in most tested combinations, and the time-kill kinetics demonstrated a pronounced bactericidal effect, achieving a ≥3 log10 reduction in bacterial counts compared to the most active single agent, with no evidence of bacterial regrowth over 24 h. It was concluded that nanosponge formulation significantly enhanced the antibacterial and antibiofilm properties of ODHP and effectively potentiated the activity of ceftriaxone against MDR K. pneumoniae. This study highlights ODHP-NS as a potential antimicrobial adjuvant for combating MDR K. pneumoniae infections.