| Abstract: | Bacterial resistance induced by the use of antibiotics has provided a chance for the development of antimicrobial peptides (AMPs), and modification of AMPs to enhance the antibacterial activity or stability has become a research focus. PMAP‐37 is an AMP isolated from porcine myeloid marrow, and studies on its modification have not yet been reported. In this study, three PMAP‐37 analogs named PMAP‐37(F9‐R), PMAP‐37(F34‐R), and PMAP‐37(F9/34‐R) were designed by residue substitution to enhance the positive charge. The antimicrobial activity of PMAP‐37 and its analogs in vitro and in vivo were detected. The results showed that compared with PMAP‐37, PMAP‐37(F9‐R) and PMAP‐37(F9/34‐R) exhibited antibacterial activity against S. flexneri CICC21534. Although PMAP‐37(F34‐R) had no antibacterial activity against S. flexneri CICC21534, its minimal inhibitory concentrations (MICs) were significantly lower than those of PMAP‐37 against most bacterial strains. Besides, all PMAP‐37 analogs were pH stable, retaining stable antibacterial activity after treatment with solution from pH 2 to pH 8/9. In addition, the PMAP‐37 analogs displayed increased thermal stability, and PMAP‐37(F34‐R) retained >60% antibacterial activity after boiling for 2 hours. Furthermore, the PMAP‐37 analogs exhibited impressive therapeutic efficacy in bacterial infections by reducing bacterial burden and inflammatory damage in the lung and liver, resulting in a reduction in mortality. Notably, the therapeutic effect of PMAP‐37(F34‐R) was comparable to that of ceftiofur sodium, and even superior to antibiotics in L. monocytogenes CICC21533 infection model. In conclusion, the PMAP‐37(F34‐R) may be a candidate for the treatment of bacterial infections in the clinic. |
