Abstract
Gramicidin A is an antimicrobial peptide that destroys gram-positive bacteria. The bactericidal mechanism of antimicrobial peptides has been linked to membrane permeation and metabolism disruption as well as interruption of DNA and protein functions. However, the exact bacterial killing mechanism of gramicidin A is not clearly understood. In the present study, we examined the antimicrobial activity of gramicidin A on Staphylococcus aureus using biochemical and biophysical methods, including hydroxyl radical and NAD+/NADH cycling assays, atomic force microscopy, and Fourier transform infrared spectroscopy. Gramicidin A induced membrane permeabilization and changed the composition of the membrane. The morphology of Staphylococcus aureus during gramicidin A destruction was divided into four stages: pore formation, water permeability, bacterial flattening, and lysis. Changes in membrane composition included the destruction of membrane lipids, proteins, and carbohydrates. Most interestingly, we demonstrated that gramicidin A not only caused membrane permeabilization but also induced the formation of hydroxyl radicals, which are a possible end product of the transient depletion of NADH from the tricarboxylic acid cycle. The latter may be the main cause of complete Staphylococcus aureus killing. This new finding may provide insight into the underlying bactericidal mechanism of gA.
Highlights
The driving force for the development of new anti-bacterial drugs is always the inevitable emergence of bacterial resistance to antibiotics following widespread clinical use [1]
We examined the antimicrobial activity of gramicidin A (gA) and studied the effect of gA on the nanostructure and composition changes of S. aureus
The antimicrobial activity of gA has been associated with membrane permeabilization, the present results further demonstrate that gA can induce the formation of hydroxyl radicals in a concentration-dependent manner, indicating that gA may perform its bactericidal activity through destroying cell membranes, and by inducing the formation of hydroxyl radicals
Summary
The driving force for the development of new anti-bacterial drugs is always the inevitable emergence of bacterial resistance to antibiotics following widespread clinical use [1]. The search for new antibiotic drugs has prompted an interest in a group of antimicrobial peptides (AMPs) [2, 3]. The source of AMPs is natural organisms, including animals, plants, or the pathogen itself [3,4,5,6,7,8]. Unlike common antibiotic drugs, which in most cases are synthesized by special metabolic pathways, the amino acid sequences of AMPs are naturally encoded in the genetic material of the host organism [3, 5, 6].
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