Advantage of a Narrow Spectrum Host Defense (Antimicrobial) Peptide Over a Broad Spectrum Analog in Preclinical Drug Development

Abstract

The APO-type proline-arginine-rich host defense peptides exhibit potent in vitro killing parameters against Enterobacteriaceae but not to other bacteria. Because of the excellent in vivo properties against systemic and local infections, attempts are regularly made to further improve the activity spectrum. A C-terminal hydrazide analog of the Chex1-Arg20 amide (ARV-1502) shows somewhat improved minimal inhibitory concentration against Moraxellaceae. Here we compared the activity of the two peptides as well as an inactive dimeric reverse amide analog in a systemic Acinetobacter baumannii infection. Only the narrow spectrum amide derivative reduced the 6-h blood bacterial burden by >2 log10 units reaching statistical significance (p = 0.03 at 5 mg/kg and 0.031 at 2 mg/kg administered intramuscularly). The hydrazide derivative, probably due to stronger activity on cell membranes, lysed erythrocytes at lower concentrations, and caused toxic effects at lower doses (10 mg/kg vs. 25 mg/kg). In a limited study, the amide induced a >5-fold production of the anti-inflammatory cytokine IL-10 over untreated naïve mice and minor increases in the anti-inflammatory IL-4 and pro-inflammatory cytokines TNF-α and IL-6, in blood. The blood of hydrazide-treated mice exhibited significantly lowered levels of IL-10 and slightly decreased IL-4 and TNF-α. These results suggest that the improved efficacy of the narrow-spectrum amide analog is likely associated with increased anti-inflammatory cytokine production and better stimulation of the immune system. Although blood IL-6 and TNF-α levels are frequently used as markers of potential toxicity in drug development, we did not observe any notable increase in mice receiving the toxic polyamide antibiotic colistin.

Low cationicity is important for systemic in vivo efficacy of database-derived peptides against drug-resistant Gram-positive pathogens

“…How to design AMPs with systemic in vivo efficacy is not clear. We found here 10,20,30,40,50,60,70,80,90, and 100 on the x axis of the plot. The sum of the averaged R% and K% from each bin is represented by the y axis.…”

“…Additional positive charges might have facilitated peptide binding to host factors in vivo, rendering them unavailable for bacterial killing. In contrast, proline-rich peptides with high positive charges but low hydrophobic amino acids may also be less favorable to bind to multiple host factors, yielding an alternative design for in vivo efficacy against Gramnegative pathogens (40)(41)(42). Collectively, these results define two biased amino acid compositions for designing narrow-spectrum peptides with systemic in vivo efficacy: low cationic databasedesigned peptides against Gram-positive pathogens and low hydrophobic proline-rich peptides against Gram-negative pathogens.…”

Efficacy of ARV-1502, a Proline-Rich Antimicrobial Peptide, in a Murine Model of Bacteremia Caused by Multi-Drug Resistant (MDR) Acinetobacter baumannii

“…It has been reported that ARV-1502 is active against a broad range of MDR Gram-negative bacterial species, including A. baumannii, P. aeruginosa, E. coli, and K. pneumoniae [18,19]. For instance, the peptide showed inhibitory activity on the growth of E. coli and K. pneumoniae strains with MIC values of 6 and 2 μg/ml, respectively [17,20].…”

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

“…including pyrrochorrycins [ 386 , 387 ], apeadicins [ 388 , 389 ], and oncocins [ 390 ]. Some of them are in a preclinical stage [ 391 , 392 ]. All of these are narrow spectral AMPs.…”

“…All of these are narrow spectral AMPs. Some were more efficient in vivo than in vitro, supposedly due to cooperation with the innate immune system of the host to be protected [ 376 , 386 , 387 , 388 , 389 , 390 , 391 , 392 ].…”