A novel in silico antimicrobial peptide DP7 combats MDR Pseudomonas aeruginosa and related biofilm infections

Abstract

Background Antimicrobial peptides are promising alternative antimicrobial agents to combat MDR. DP7, an antimicrobial peptide designed in silico, possesses broad-spectrum antimicrobial activities and immunomodulatory effects. However, the effects of DP7 against Pseudomonas aeruginosa and biofilm infection remain largely unexplored. Objectives To assess (i) the antimicrobial activity of DP7 against MDR P. aeruginosa; and (ii) the antibiofilm activity against biofilm infection. Also, to preliminarily investigate the possible antimicrobial mode of action. Methods The MICs of DP7 for 104 clinical P. aeruginosa strains (including 57 MDR strains) and the antibiofilm activity were determined. RNA-Seq, genome sequencing and cell morphology were conducted. Both acute and chronic biofilm infection mouse models were established. Two mutants, resulting from point mutations associated with LPS and biofilms, were constructed to investigate the potential mode of action. Results DP7, at 8–32 mg/L, inhibited the growth of clinical P. aeruginosa strains and, at 64 mg/L, reduced biofilm formation by 43% to 68% in vitro. In acute lung infection, 0.5 mg/kg DP7 exhibited a 70% protection rate and reduced bacterial colonization by 50% in chronic infection. DP7 mainly suppressed gene expression involving LPS and outer membrane proteins and disrupted cell wall structure. Genome sequencing of the DP7-resistant strain DP7R revealed four SNPs controlling LPS and biofilm production. gshA44 and wbpJ139 mutants displayed LPS reduction and motility deficiency, conferring the reduction of LPS and biofilm biomass of strain DP7R and indicating that LPS was a potential target of DP7. Conclusions These results demonstrate that DP7 may hold potential as an effective antimicrobial agent against MDR P. aeruginosa and related infections.

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

“…In acute lung infection, it exhibited a 70% protection rate and reduced bacterial colonization by 50% in chronic infection. It mainly suppressed gene expression involving lipopolysaccharide (LPS) and outer membrane proteins and disrupted cell-wall structure [ 80 ]. Recently, a great deal of effort has been directed towards the problem of fighting against biofilm formation by bacteria.…”

Diverse Antibacterial Treatments beyond Antibiotics for Diabetic Foot Ulcer Therapy

“…[93] Qi et al designed a broad-spectrum AMP named DP7 (VQWRIRVAVIRK), which showed great potential against multiple pathogens including MDR P. aeruginosa and related biofilm infections. [94,95] Most AMPs take effect against P. aeruginosa biofilms with a high minimal biofilm inhibitory concentration (MBIC) value, usually tens to hundreds times their MIC, such as the amphibian peptide esculentin and bacterial peptide P128. [96,97] Even the well-known Bac2A (RLARIVVIRVAR) and HH2 (VQLRIRVAVIRA) couldn't inhibit biofilm formation at low concentration against P. aeruginosa, while DP7 presented an 30% biofilm inhibitory effects at 1/2 of its MIC.…”

Antimicrobial Peptides: From Design to Clinical Application

“…For example, two AMP motifs (A15_B and A15_E) were screened by the Support Vector Machines algorithm from Pleurocidin, an AMP found in fish, displayed antimicrobial potentials in silico [101]. Research studies showed that DP7, an AMP designed in silico, showed broad-spectrum antimicrobial activity against MDR bacteria, such as P. aeruginosa [102]. Currently, there are many antimicrobial peptides databases (APDs) such as APD3 [63] and collection of antimicrobial peptides (CAMP)R3 [103], as well as online tools for AMP screening and identification such as dbAMP [104] and Ensemble-AMPPred [105].…”