The Dawn of Novel Drug Targets and Drugs
Author: Vipin Chandra Kalia

Introduction

All living beings need to maintain their identity and integrity. They have developed their arsenal to protect themselves and attack others, if needed. However, almost all of them depend up on others for survival. Hence, there are interactions which are mutually beneficial. Microbes interact with plants especially in the rhizosphere and phyllosphere and exchange nutrients. Microbial interactions with animals extend from skin surface to gut. However, beyond these benign relationships, microbes infect on plants and animals including human beings and become pathogenic. They derive nutrition by eating up the cells of the host organism. In order to prevent the spread of the pathogenic organism, antibiotics have been the most effective. However, the efficiency of the antibiotics as drugs has been challenged by microbes, as they rapidly undergo genetic changes. Microbes become resistant to antibiotics and we are forced to look for novel antibacterial drugs. It has been realized that microbes mutate under heavy environmental pressure, which threatens their survival and may be existence. As an alternative, vaccines were developed. This route has been rather slow and difficult. Now, researchers have come across another scenario, where pathogens are not stressed to the extent where they may die. Instead of killing the pathogens, the strategy is to inhibit the infection process and stop bacteria from expressing their pathogenecity. It has been realized that almost 65% of the infectious diseases are caused by bacteria through the cell density dependent phenomenon of Quorum sensing.

Quorum sensing

Many bacteria express their genes responsible for causing pathogenecity only when they have achieved a population density which is high enough to produce enzymes in quantities, which are sufficient to kill the host cell. The bacteria continue to multiply silently and release signal molecules. These signal molecules are sensed by the receptors on the cell surface. It helps them to sense their population density. This phenomenon is termed as Quorum Sensing. Once the quorum is complete, signal molecules are retrieved in to the cell and transcription of genes responsible for expression of pathogenecity is initiated.

Novel Drug Targets and Drugs

Quorum sensing (QS) signal molecules are the major cause of biofilm formation. Biofilms act as shields, which prevent bacteria from the action of antibiotics. Bacteria within bioflm can withstand up to 1000 times higher antibiotic concentrations compared to their planktonic counter parts. Thus, QS signal molecules have been perceived as potential novel drug targets to prevent biofilm formation, which thus makes bacteria susceptible to lower doses of antibiotics. Among a host of QS signal molecules, the most frequently encountered are the acyl-homoserine lactones (AHLs), which are composed of a lactone ring and a variable carbon length acyl chain. The AHLs can be inactivated by the enzymes: (i) lactonases, and (ii) acylases.

AHL-lactonases

AHL– lactonase enzyme disrupts the signal molecule by opening up the ring structure. Once inactivated, the AHL signal molecule is not able to operate the QS system gene expression. This gene for this enzyme is prevalence among Gram-positive (especially Firmicutes) and Gram-negative (largely Proteobacteria). The genetic variation for AHL-lactonase has been reported among: Bacillus, Lysinibacillus,Deinococcus radiodurans, Acidobacteria,Agrobacterium, Arthrobacter,Bradyrhizobium, Klebsiella, Rhodococcus, Stappia, Thermoplasma, and Halomonas.

AHL-acylases

AHL-acylase acts by cleaving the side chain of the signal molecule. These enzymes are more specific as these are governed by the length of the acyl chain. The organisms found to possess these enzymes have been found to belong to: (a) Ralstonia sp., (b) Azotobacter vinelandii, (c) Pseudomonas sp., (d) D. radiodurans, (e)Streptomyces sp. (f) Cyanothece sp., (g)Crocosphaera watsonii, (h) Comamononas, (i) Shewanella, (j) Anabaena, and (k) Alteromonas.

The Evidences of Potentiality

  1. Lactonases expressed in tobacco and potato plants imparts them with resistance to – Erwinia cartovora. Bacillus lactonases protect fish and fresh water prawn from Vibrio and Aeromonas hydrophila infections.

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About Author / Additional Info:
Researcher in Microbial Biotechnology and Genomics at CSIR-IGIB, Delhi.