Antibiotic resistance in Acinetobacter baumannii is on the rise around the world, highlighting the urgent need for novel antimicrobial drugs. Antimicrobial peptides (AMPs) contribute to effective protection against infections by pathogens, making them the most promising options for next-generation antibiotics. Here, we report two designed, cationic, antimicrobial-derived peptides: Mt6, and its dextroisomer D-Mt6, belonging to the analogs of MAF-1, which is isolated from the instar larvae of houseflies. Both Mt6 and D-Mt6 have a broad-spectrum antimicrobial activity that is accompanied by strong antibacterial activities, especially against A. baumannii planktonic bacteria and biofilms. Additionally, the effect of D-Mt6 against A. baumannii is stable in a variety of physiological settings, including enzyme, salt ion, and hydrogen ion environments. Importantly, D-Mt6 cleans the bacteria on Caenorhabditis elegans without causing apparent toxicity and exhibits good activity in vivo. Both Mt6 and D-Mt6 demonstrated synergistic or additive capabilities with traditional antibiotics against A. baumannii, demonstrating their characteristics as potential complements to combination therapy. Scanning electron microscopy (SEM) and laser scanning confocal microscope (LSCM) experiments revealed that two analogs displayed rapid bactericidal activity by destroying cell membrane integrity. Furthermore, in lipopolysaccharide (LPS)-stimulated macrophage cells, these AMPs drastically decreased IL-1β and TNF-a gene expression and protein secretion, implying anti-inflammatory characteristics. This trait is likely due to its dual function of directly binding LPS and inhibiting the LPS-activated mitogen-activated protein kinase (MAPK) signaling pathways in macrophages. Our findings suggested that D-Mt6 could be further developed as a novel antimicrobial/anti-inflammatory agent and used in the treatment of A. baumannii infections. IMPORTANCE Around 700,000 people worldwide die each year from antibiotic-resistant pathogens. Acinetobacter baumannii in clinical specimens increases year by year, and it is developing a strong resistance to clinical drugs, which is resulting in A. baumannii becoming the main opportunistic pathogen. Antimicrobial peptides show great potential as new antibacterial drugs that can replace traditional antibiotics. In our study, Mt6 and D-Mt6, two new antimicrobial peptides, were designed based on a natural peptide that we first discovered in the hemlymphocytes of housefly larvae. Both Mt6 and D-Mt6 showed broad-spectrum antimicrobial activity, especially against A. baumannii, by damaging membrane integrity. Moreover, D-Mt6 showed better immunoregulatory activity against LPS induced inflammation through its LPS-neutralizing and suppression on MAPK signaling. This study suggested that D-Mt6 is a promising candidate drug as a derived peptide against A. baumannii.

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