Life-threatening infectious diseases are on their way to cause a worldwide crisis, as treating them effectively is becoming increasingly difficult due to the emergence of antibiotic resistant strains. Antimicrobial peptides (AMPs) form an ancient type of innate immunity found universally in all living organisms, providing a principal first-line of defense against the invading pathogens. The unique diverse function and architecture of AMPs has attracted considerable attention by scientists, both in terms of understanding the basic biology of the innate immune system, and as a tool in the design of molecular templates for new anti-infective drugs. AMPs are gene-encoded short (<100 amino acids), amphipathic molecules with hydrophobic and cationic amino acids arranged spatially, which exhibit broad spectrum antimicrobial activity. AMPs have been the subject of natural evolution, as have the microbes, for hundreds of millions of years. Despite this long history of co-evolution, AMPs have not lost their ability to kill or inhibit the microbes totally, nor have the microbes learnt to avoid the lethal punch of AMPs. AMPs therefore have potential to provide an important breakthrough and form the basis for a new class of antibiotics. In this review, we would like to give an overview of cationic antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which are highly expressed and found in humans, as well as a brief discussion about widely abundant, well characterized AMPs in mammals, in addition to pharmaceutical aspects and the additional functions of AMPs.

Optimization of production medium is required to maximize the metabolite yield. This can be achieved by using a wide range of techniques from classical “one factor-at-a-time” to modern statistical and mathematical techniques, viz. artificial neural network, genetic algorithm etc. Each technique has its own advantages and disadvantages, and there are the situations where these techniques are applied for obtaining best results. Use of various optimization techniques in combination also provides the required results. In this article an attempt has been made to review the currently used media optimization techniques applied during fermentation process of metabolite production. Comparative analysis of the merits and the demerits of various conventional as well as modern optimization techniques have been done and logical selection basis has been given in the present review. This review will provide the rationale of selection of suitable technique for the media optimization employed during the fermentation process of metabolite production.

Methods for increasing the proteolytic stability of EFK17 (EFKRIVQRIKDFLRNLV), a new peptide sequence with antimicrobial properties derived from LL-37, were evaluated. EFK17 was modified by four d-enantiomer or tryptophan (W) substitutions at known protease cleavage sites as well as by terminal amidation and acetylation. The peptide variants were studied in terms of proteolytic resistance, antibacterial potency, and cytotoxicity but also in terms their adsorption at model lipid membranes, liposomal leakage generation, and secondary-structure behavior. The W substitutions resulted in a marked reduction in the proteolytic degradation caused by human neutrophil elastase,Staphylococcus aureusaureolysin, and V8 protease but not in the degradation caused byPseudomonas aeruginosaelastase. For the former two endoproteases, amidation and acetylation of the terminals also reduced proteolytic degradation but only when used in combination with W substitutions. The d-enantiomer substitutions rendered the peptides indigestible by all four proteases; however, those peptides displayed little antimicrobial potency. The W- and end-modified peptides, on the other hand, showed an increased bactericidal potency compared to that of the native peptide sequence, coupled with a moderate cytotoxicity that was largely absent in serum. The bactericidal, cytotoxic, and liposome lytic properties correlated with each other as well as with the amount of peptide adsorbed at the lipid membrane and the extent of helix formation associated with the adsorption. The lytic properties of the W-substituted peptides were less impaired by increased ionic strength, presumably by a combination of W-mediated stabilization of the largely amphiphilic helix conformation and a nonelectrostatic W affinity for the bilayer interface. Overall, W substitutions constitute an interesting means to reduce the proteolytic susceptibility of EFK17 while also improving antimicrobial performance.

The coagulation system is characterized by the sequential and highly localized activation of a series of serine proteases, culminating in the conversion of fibrinogen into fibrin, and formation of a fibrin clot. Here we show that C-terminal peptides of thrombin, a key enzyme in the coagulation cascade, constitute a novel class of host defense peptides, released upon proteolysis of thrombin in vitro, and detected in human wounds in vivo. Under physiological conditions, these peptides exert antimicrobial effects against Gram-positive and Gram-negative bacteria, mediated by membrane lysis, as well as immunomodulatory functions, by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, they are protective against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock. Moreover, the thrombin-derived peptides exhibit helical structures upon binding to lipopolysaccharide and can also permeabilize liposomes, features typical of “classical” helical antimicrobial peptides. These findings provide a novel link between the coagulation system and host-defense peptides, two fundamental biological systems activated in response to injury and microbial invasion. Wounding of the skin and other epithelial barriers represents an ever-present challenge and poses a potential threat for invasive infection and sepsis. Therefore, it is not surprising that evolutionary pressure has maintained and developed multiple host defense systems, involving initial hemostasis and fibrin formation, and the subsequent action of multiple proteins and peptides of our innate immune system. In humans, the coagulation pathways and those mediating innate immune responses to infections have so far been seen as separate entities. This view is challenged by the present study, which discloses novel host defense functions of C-terminal peptides of thrombin, a key enzyme in the coagulation cascade. The thrombin-derived peptides, which are detected in human wounds and fibrin, effectively kill microbes by membrane lysis, but also exert potent immunomodulatory and anti-endotoxic functions. Importantly, these peptides protect against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock in animal models. Thus, from the perspective of wounding and infection, thrombin, after fulfilling its primary function by generating a first line of defense, the fibrin clot, serves an additional role by the generation of antimicrobial and anti-endotoxic host-defense peptides.