Synergy of antimicrobial peptides.

Abstract

Abstract Emerging multidrug-resistant organisms challenge the medical community to search for new, effective antimicrobial agents to combat infection. Antimicrobial peptides (AMPs) offer a solution for this challenge and could play a major role in the search for new therapeutic regimens against MDR organisms. These peptides can be utilized in their natural or in synthetic forms, or modulated by agents increasing their natural production in vivo via altered gene regulation. Combinations of AMPs with conventional antibiotics and duplicate and triplicate combinations of AMPs are effective in combating Gram-positive and Gramnegative bacteria, as well as parasites and fungi. AMPs of different classes as well as a common class can be combined to induce synergy, enhancing the antimicrobial activity of each peptide or antibiotic compared with its activity alone. Although some specific triple AMP combinations are more effective than specific double AMP combinations, enhancement is generally not a simple stoichiometric relationship. The synergy between AMPs is complex and depends on the concentration and the combination of specific AMPs. Mechanisms include combining membrane-permeabilizing activities as well as modulating the innate immune system to combat inflammatory activity induced by the microorganisms. Mechanisms of AMP-enhanced antibiotic activity are not well studied, although it is postulated that the membrane altering effects allow for increased permeabilization of the membrane to the antibiotic, enhancing antimicrobial activity. Combinations of AMPs with conventional antibiotics serve the advantage of overcoming microbial resistance to the antibiotic as well as decreasing some of the toxicity of certain antibiotics in the patient. Creation of chemical compounds, termed AMP mimetics, that could replace AMPs known to combine with antibiotics to enhance activity would be advantageous in solving the problem of economically feasible AMP production. The examination of synergy with this new class of antibiotics is needed, for the pharmacodynamics of synergy and antagonism between combinations of these agents is complex and varies with the specific combination of agents. So far, research results demonstrate that synergy between AMPs or their mimetics, between themselves or with existing antibiotics offers a solution to the antibiotic resistance problem.