SMAP29: an antibacterial peptide that possesses anti-inflammatory and fast bactericidal actions against colistin-resistant gram-negative bacteria.

UNLABELLED: Multidrug-resistant (MDR) gram-negative bacteria (GNB) are threatening global public health. Since colistin (COL) is the last resort antibiotic for MDR gram-negative infections, the rise in colistin-resistant ‌(COL-R) bacteria could pose risks to people. The current research investigation explored the antimicrobial, anti-biofilm, and anti-inflammatory capacities of SMAP29, a naturally generated cationic antibacterial peptide, against clinical COL-R Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, and explored its antibacterial mechanisms. The results demonstrated that SMAP29 exhibited a very low minimum inhibitory concentration against COL-R GNB and rapidly killed bacteria within 30 min. In addition, SMAP29 inhibited biofilm growth and eliminated it. According to another study's findings, SMAP29 could lead to the membrane's integrity being wiped out, which could result in the formation of intracellular reactive oxygen species. Moreover, SMAP29 could effectively prevent RAW 264.7 macrophages in mice from generating the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Assays for cytotoxicity and hemolysis in vitro revealed that SMAP29 proved safe at the tested concentrations. In vivo experiments further demonstrated that the amount of bacteria in the infected mice's thighs was significantly reduced through SMAP29 treatment. Collectively, our findings demonstrate that SMAP-29's efficacy stems from its dual action: rapid bactericidal activity via lipopolysaccharide-mediated membrane disruption and concurrent anti-inflammatory effects. This multifaceted potency, validated both in vitro and in vivo, positions SMAP-29 as a promising therapeutic candidate against multidrug-resistant bacterial infections.

IMPORTANCE: Multidrug-resistant gram-negative bacteria have emerged as critical threats to global public health, driving intractable infections with steadily rising incidence. These pathogens exhibit formidable tolerance to virtually all classes of contemporary antibiotics, translating into persistently high mortality and formidable clinical challenges. This study elucidates the antibacterial, anti-biofilm, and anti-inflammatory activities of the antimicrobial peptide SMAP-29 against colistin-resistant gram-negative organisms while dissecting its underlying mechanisms. Our findings provide a mechanistic framework and a promising therapeutic avenue for combating multidrug-resistant infections.