Antimicrobial proteins
Antimicrobial proteins are one of the most primitive wings of immune system acting against invading pathogen. They are naturally occurring antibiotics, regulating both innate and adaptive immunity. During mycobacterial infection, neutrophil granular proteins such as cathelicidins, azurocidin, cathepsin, and lactoferrin cause activation of macrophages leading to intracellular killing of the pathogen. Similarily lactoferrin and calprotectin cause chelation of metals ions essential for mycobacterial growth and survival. Defensins and eosinophil granular proteins i.e ECP and EPO bring about direct killing of mycobacteria by altering bacterial membrane permeability. Other than the bactericidal action, proteins such as NE and HNP decrease the bacterial burden inside lungs by providing protective immunity against the pathogen. Though several of AMPs have shown promising results for drug developement, but only few have reached the clinical trial phase (Table 1). hLF-11 derived from lactoferrin has been found to be effective against multi-drug resistant S.aureus (MRSA). hLF-11 has entered clinical phase I study for treatment of common hospital bacterial infections.142 Cathelicidin from snake venom with its anti-microbial and anti-inflammatory effects has found therapeutic use against acne vulgaris.143 Pexiganan, a synthetic analogue of Xenopus derived magainins, was topically applied for the treatment of diabetic foot ulcers.144 Thus usage of AMP's and their derivatives for therapeutic purpose is slowly picking up pace, as vivid from the list of AMPs entered in clinical trials.
The rationale of development of new and effective drugs is fast losing the battle against superbugs, such as S.aureus and Mtb. In case of Mtb, an unprecedented use of available antibiotics has evolved into a deadly strain resistant to all the first and second line drugs. There is a growing perception for the consideration of AMPs as alternative for the conventional drugs. AMP offers an array of advantages over available conventional drugs. Majority of the AMP's have their targets as cell membrane and intracellular molecules. The first major advantage of AMP's over other drugs is their specificity in inhibiting or killing the pathogen with limited toxicity to the host cells in the proximity. The differential membrane composition, hydrophobicity, charge between the host cell and microbial membrane allows AMP to distinguish between the two.145 Moreover development of resistance against these peptides is difficult owing to their rapid bactericidal action.146 High bacterial membrane binding property due to net positive charge, small size, ability to from pores are various other factors that make AMPs much better than the conventional drugs.147 The potential advantages and disadvantages of inclusion of AMPs as therapeutics are given in Table 3. But before using AMP's therapeutically, disadvantages linked to their usage have to be looked into. The primary challenge would be obtaining enough amounts of the protein to reach the intracellular targets, making it expensive as compared to the drugs. Secondly they have a short half-life and get degraded easily under normal physiological conditions. So the future strategy should be to encapsulate them with carrier molecules such as biodegradable nanoparticles that would increase their half-life and retain their viability without being cytotoxic to host cells. Moreover a synergistic approach using both drugs and AMP's has shown promising results with enhanced bactericidal action , and prevention of development of drug-resistance.149 Recently we have shown that cationic AMPs in combination with biogenic nanoparticles enhance killing of mycobacteria without harming host cells.12 In conclusion, though the therapeutic application of AMP's hold immense potential, it is imperative to improve the application to meet the need for new drugs especially against pathogens such as Mycobacterium to face the menace of drug resistance in hand.