Over 9.5 million people die each year due to infectious diseases –
nearly all live in developing countries.The scientific efforts of the
last 50 years centered on about a dozen antimicrobial core chemotype
scaffolds such as sulfa drugs (1936), ß-lactams (1940), chloramphenicol
and tetracycline (1949), aminoglycosides (1950), macrolides (1952),
glycopeptides (1952), quinolones (1962), and oxazolidinones (2000). The
problems associated with these scaffolds are: a) widespread antibiotic
resistance, b) emergence of new pathogens in addition to the resurgence
of old ones, and c) the lack of effective new therapeutics in these
classes. So, novel agents are required which are not only effective
against resistant micro-organism but should also less susceptible to
drug resistance. Antimicrobial peptides belong to one such novel class.
Antimicrobial Peptides (AMPs)
They
are endogenous peptides and are major component of innate self-defense
system. These peptides are potent, broad spectrum antibiotics and have
been demonstrated to kill wide range of micro-organisms and cancerous
cells.
Why Peptides?
? Broad-spectrum activity (antibacterial, antiviral, antifungal).
? Rapid onset of killing.
? Bactericidal activity.
? Potentially low levels of induced resistance.
? Concomitant broad anti-inflammatory activities
? Development of resistance is improbable.
Sources of AMPs
A
variety of AMPs and proteins have been isolated from virtually all the
kingdoms and phyla including plants, microbes, insects, animals and
humans. Given below is a list of AMPs classified based on their
molecular structure along with their source and activity
Properties of AMPs
AMPs
have a net positive charge and they contain both hydrophilic and
hydrophobic side chains. The peptide adopts a shape in which clusters of
hydrophobic (inserts in lipid membrane) and cationic amino acids (binds
to negative membrane) are spatially organized in discrete sectors of
the molecule (‘amphipathic’ design).
Biological action of AMPs
Shai-Matsuzaki-Huang
model for the mechanism of antimicrobial peptide can be described as
follows: the first step involves electrostatic interaction of the
positively charged peptide molecule with the negatively charged
bacterial membrane (a);integration of the peptide into the membrane (b).
At this point there is increase in the surface area of the cell
membrane;formation of transient ores (worm-hole) (c); peptide
transported to the inner side of membrane (d). At this point two
mechanisms can take place (membrane disruptive or non-disruptive);
peptide molecules translocate to the intracellular targets
(non-disruptive) (e); peptide disrupts the cell membrane (f).
Basis for the design of short AMPs
Larger
peptide suffers from the problems like high cost of discovery and
synthesis,systemic and local toxicity, susceptibility to proteolysis,
pharmacokinetic (PK) and pharmacodynamic (PD) issues, sensitization and
allergy after repeated application, natural resistance (e.g.,
Serratiamarcescens), lack of in vitro to invivo correlation and high
manufacturing costs. It is therefore important to develop smaller
antimicrobial peptides. Svendsen and co-workers synthesized a number of
short cationic AMPs and reported “Trp-Arg” class to be active against
Staphylococcus aureus (MIC value 10 µg/mL. Further more co-workers
reported “Trp-His” and “His-Arg” class of dipeptides to be active
against a wide micro-organism (MIC = 5-20 µg/mL, IC50 = 1-5 µg/mL).These
peptides have small size, contains unnatural amino acids, have high
antimicrobial activity and absence of cytotoxicity which suggests that
they can be future drugs for antimicrobial therapeutics.
Drug Development of AMPs
Peptides
are not considered as ideal drug molecules as they are readily cleaved
by enzymes when administered orally (however they are used topically in
the form of creams and solutions). But modern formulation science has
made the oral administration of peptides a reality. Two cationic
peptides namely gramicidin S, and polymyxin B are currently used as
antimicrobials in the form of topical creams and solution
(systematically they are very toxic and hence not used). Colomycin
(prodrug of polymyxin E) is used systematically as anti-infective agent.
It has been reported that several AMPs exhibit antimicrobial effect
against sexually transmitted pathogen and are also known to possess
contraceptive activity.Furthermore many cationic peptides are in
clinical trials.
Conclusions
Antibiotics are widely
used for the therapeutics of microbial infections. But the resistance to
currently used drugs necessitates novel classes of drugs to be
developed. Cationic AMPs belongs to one such class. But such larger
peptide also suffers from problem like high cost of synthesis, less in
vitro in vivo correlation, which limits their systemic use. So smaller
cationic AMPs are required that can be used systemically. Earlier
research already proved that very small yet biologically active AMPs can
be produced which are enzymatically stable and relatively easy to
synthesize with good antimicrobial activity and no apparent
cytotoxicity. These findings make future research in the area of AMPs
exciting.
Rahul Jain is professor and Mohit Gupta &
Vijay Kanani are third semester MS students in the Department of
Medicinal Chemistry,NIPER ,S.A.S.Nagar, Mohali,Punjab.