Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus (original) (raw)

Abstract

The emergence of global antibiotic resistance necessitates the urgent need to develop new and effective antimicrobial agents. Combination of two antimicrobial agents can potentially improve antimicrobial potency and mitigate the development of resistance. Therefore, we have utilized metal molecular doping methodology whereby antimicrobial random peptides mixture (RpMs) are entrapped in a bactericidal copper metal matrix. The copper/RPM composite exhibits greater antimicrobial activity toward methicillin-resistant Staphylococcus aureus (MRSA) than either copper or RPMs alone. Our findings indicate that this bactericidal antimicrobial biomaterial could be utilized to efficiently eradicate antibiotic-resistant pathogenic bacteria for health, agricultural and environmental applications. Bacterial resistance to antibiotics is a global concern and there is a continuing need to the develop new antimicrobial agents. Resistant bacteria in both hospitals and the environment cause prolonged hospitalization and the death of tens of thousands of people annually, worldwide. For example, methicillin-resistant Staphylococcus aureus (MRSA) claims the lives of approximately 19,000 people per annum in the United States alone 1. Current solutions to this global crisis includes the use of new classes of antimicrobial agents and traditional bactericides 1. The combination of two antimicrobial agents that possess different modes of action has been suggested as a more effective solution to eradicate resistant bacteria than using just one 2,3. Low concentrations of metals such as copper and silver exhibit bactericidal properties and are thought to work either extracellularly by binding and inactivating membrane proteins or intracellularly after transport into the cell 4,5. In fact, copper has been used in ancient Egypt as early as 2000 B.C. to sterilize water and wounds 6. Although silver has greater bactericidal activity, copper is less expensive and therefore utilized extensively in both the health and agricultural sectors 7,8. For example, it has been used as an additive in water treatment facilities, as a disinfectant in the food industry, for hospital sterilization, to incorporate antifouling properties in paint and for wound healing 6,9. Copper is also commonly used on a large scale in the agricultural sector for crop protection 6,10. The microbial toxicity of copper is mediated through multifactorial pathways, one of which exploits its ability to act as a catalyst to generate reactive oxygen species (ROS), which cause damage to vital cell constituents such as proteins, lipids and DNA 5,7,11. Copper ions can also deactivate intracellular and membrane proteins by direct interaction or via competition for the binding sites of essential metals. In both cases, inhibition or deactivation of the protein is the result of conformational changes in the protein structure 6,7. Unfortunately, copper-resistant bacterial strains have emerged and are responsible for significant reductions in crop yields 9,12 , therefore, there is an urgent need for novel solutions to combat these resistant pathogens 5. This has spurred study of its antimicrobial or anti-biofilm activity together with combinations of amino acids 13 , organic acids 14 , hepcidin 15 or copper binding peptides 16,17. Here, we present a new combination of antimicrobial agents: a copper matrix doped with antimicrobial peptides.

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