Antimicrobial Peptides Demonstrate Activity against Resistant Bacterial Pathogens

Abstract

The antimicrobial resistance crisis is an ongoing major threat to public health safety. Low- and middle-income countries are particularly susceptible to higher fatality rates and the economic impact of antimicrobial resistance (AMR). As an increasing number of pathogens emerge with multi- and pan-drug resistance to last-resort antibiotics, there is an urgent need to provide alternative antibacterial options to mitigate disease transmission, morbidity, and mortality. As identified by the World Health Organization (WHO), critically important pathogens such as Klebsiella and Pseudomonas species are becoming resistant to last-resort antibiotics including colistin while being frequently isolated from clinical cases of infection. Antimicrobial peptides are potent amino acid sequences produced by many life forms from prokaryotic, fungal, plant, to animal species. These peptides have many advantages, including their multi-hit mode of action, potency, and rapid onset of action with low levels of resistance being evident. These innate defense mechanisms also have an immune-stimulating action among other activities in vivo, thus making them ideal therapeutic options. Large-scale production and formulation issues (pharmacokinetics, pharmacodynamics), high cost, and protease instability hinder their mass production and limit their clinical application. This review outlines the potential of these peptides to act as therapeutic agents in the treatment of multidrug-resistant infections considering the mode of action, resistance, and formulation aspects. Clinically relevant Gram-positive and Gram-negative pathogens are highlighted according to the WHO priority pathogen list.

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“…Particularly concerning is the emerging resistance to last resort antibiotics, kept for cases where traditional treatments have failed 46 . We find seven Enterobacteriaceae species with extreme resistance to the last resort antibiotic Polymyxin, six to Carbapenem, and four to Fosfomycin, with two other species very close by - currently holding resistance to Fosfomycin in 89% of their strains.…”

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“…Both the WHO bacterial and fungal priority pathogen lists detail critically and highly important pathogens displaying high levels of AMR where treatment protocols are increasingly difficult to determine [ 15 ]. The ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens are nosocomial and associated with high levels of resistance and increased morbidity and mortality [ 15 ]. Clinical isolates of ESKAPE pathogens have proven to be MDR, extensively drug-resistant (XDR), and pan-drug-resistant (PDR) [ 16 ].…”

“…Small-colony variants of S. aureus have also emerged, which are causative of persistent difficult-to-treat dermal infections, with S. aureus bacteremia having a ca. 30% mortality rate [ 15 ]. The CDC reports that A. baumannii caused 8500 HAI cases and 700 deaths, ESBL Enterobacterale caused 197,400 cases and 9100 deaths, MDR P. aeruginosa caused 32,600 cases and 2700 deaths, with CRE causing 13,100 HAI cases and 1100 deaths in 2017 in the US [ 18 ].…”

“…However, these therapeutics have biocompatibility relating to kidney and liver toxicity, with resistance also emerging in some species [ 25 ]. Colistin resistance in A. baumannii results from the loss of lipopolysaccharide (LPS) from the bacterial cell membrane [ 15 ]. There are increasing rates of acquisition of a plasmid-mediated imipenem-hydrolyzing enzyme (KPC-2) by numerous Carbapenem-resistant species, including Klebsiella [ 23 ].…”

“…AMPs are positively charged (cationic) peptides averaging ca. 30 amino acids in length [ 15 ]. Anionic AMPs containing acidic amino acids, e.g., glutamic acid, also exist [ 70 ].…”