The Demand for New Antibiotics: Antimicrobial Peptides, Nanoparticles, and Combinatorial Therapies as Future Strategies in Antibacterial Agent Design

Abstract

The inappropriate use of antibiotics and an inadequate control of infections have led to the emergence of resistant strains which represent a major threat to public health and the global economy. Therefore, research and development of a new generation of antimicrobials to mitigate the spread of antibiotic resistance has become imperative. Current research and technology developments have promoted the improvement of antimicrobial agents that can selectively interact with a target site (e.g., a gene or a cellular process) or a specific pathogen. Antimicrobial peptides and metal nanoparticles exemplify a novel approach to treat infectious diseases. Nonetheless, combinatorial treatments have been recently considered as an excellent platform to design and develop the next generation of antibacterial agents. The combination of different drugs offers many advantages over their use as individual chemical moieties; these include a reduction in dosage of the individual drugs, fewer side effects compared to the monotherapy, reduced risk for the development of drug resistance, a better combined response compared to the effect of the individual drugs (synergistic effects), wide-spectrum antibacterial action, and the ability to attack simultaneously multiple target sites, in many occasions leading to an increased antibacterial effect. The selection of the appropriate combinatorial treatment is critical for the successful treatment of infections. Therefore, the design of combinatorial treatments provides a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic mechanisms of action, and better efficacy against multidrug-resistant bacteria.

Keywords: ESKAPE; MDR; XDR; antimicrobial peptides; combinatorial treatments; metal nanoparticles.

FIGURE 1

Mechanism of antimicrobial action in bacteria: (A) General mechanisms of action of antimicrobial peptides (AMPs). AMPs act through different mechanisms (Le et al., 2017) such as 1. Alteration in membrane integrity via electrostatic interaction with negatively charged cell membranes which kill cells, 2. Inhibition of DNA synthesis by (i) cross-linking with single- or double-stranded DNA, (ii) prevention of the DNA relaxation by inactivation of DNA topoisomerase I, and (iii) blocking of DNA replication by trapping the gyrase-DNA complex; and protein synthesis by (i) inhibition of protein translation by targeting the ribosomes, (ii) interrupting the protein-folding pathway, and (iii) rapid proteolytic activity causing the degradation of some DNA replication-associated proteins, leading to secondary inhibition of DNA synthesis, 3. Inhibition of bacterial cell wall formation by alteration of the alternating amino sugars in linear form that cross-link via peptide bridges to form the peptidoglycan layer, and 4. Inhibition of metabolic pathways by alteration of nucleic acid metabolism, including nucleotide transport and metabolism, nucleobase, nucleoside, and nucleotide interconversion. (B) Mechanisms for antimicrobial action of metal nanoparticles (MNPs). MNPs act via the following (Shaikh et al., 2019). 1. MNPs disturb cell membrane permeability by interfering with metabolic pathways and inducing changes in membrane shape and function. 2. When MNPs are in solution, metal ions are released in the environment surrounding. Metal ions generate reactive oxygen species (e.g., oxygen ions and hydroxyl radicals) and induce oxidative stress in bacteria. Oxidative stress is a key contributor in altering the bacterial membrane permeability and thus can damage cell membranes. Also, metal ions may cause cell structural changes and aberrant enzyme activities, which perturb normal physiological processes. 3. Interaction with sulfur- and phosphorous-containing compounds such as DNA, which prevent DNA from unwinding and transcription.

FIGURE 2

Antimicrobial treatment strategies: (A) disadvantages of using single drugs and (B) advantages of using combinatorial treatments. The advantage of using combinatorial treatments of synergistic drug pairs provides the opportunity to lower the dosage of the individual agents, thereby reducing toxicity while maintaining the wanted effect on bacteria. Moreover, a synergistic response can occur because of complementary drug action (multiple targets sites on the same protein or pathway are hit; Pemovska et al., 2018). By combining two drugs that achieve the same effect through different mechanisms of action, the development of resistance to a single drug in the combination may be less likely to occur, and when it does occur, it may have a lower impact on the therapeutic outcome (Pirrone et al., 2011). Finally, the use of more than one agent broadens the antibacterial spectrum of the empirical therapy and thus ensures that at least one agent will cover the infecting organism (Gurjar et al., 2014).