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The Dawn of Novel Drug Targets and Drugs

BY: Vipin Chandra Kalia | Category: Environmental-Biotechnology | Submitted: 2017-02-15 12:24:27
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Article Summary: "Bacteria seem to be a constant threat to the existence of human beings. We search anti-bacterials to attack bacteria and they develop resistance. No body is winning this battle. The best way is to let bacteria grow and stop their pathogenecity. Here, are the novel tools to achieve this: Live and Let Live - Fool the bacteria and .."

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


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– 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-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.

    Alipiah NM, Shamsudin MN, Yusoff FM, Arshad A (2015) Membrane biosynthesis gene disruption in methicillin-resistant Staphylococcus aureus (MRSA) as potential mechanism for reducing antibiotic resistance. Indian J Microbiol 54:41-49. doi: 10.1007/s12088-014-0488-2
  2. Arasu MV, Al-Dhabi NA, Rejiniemon TS, Lee KD, Huxley VAJ, Kim DH, Duraipandiyan V, Karuppiah P, Choi KC (2015) Identification and characterization of Lactobacillus brevis P68 with antifungal, antioxidant and probiotic functional properties. Indian J Microbiol 55:19-28. doi: 10.1007/s12088-014-0495-3
  3. Gui Z, Wang H, Ding T, Zhu W, Zhuang X, Chu W (2014) Azithromycin reduces the production of α-hemolysin and biofilm formation in Staphylococcus aureus. Indian J Microbiol 54:114-117. doi: 10.1007/s12088-013-0438-4
  4. Hema M, Balasubramanian S, Princy SA (2015) Meddling Vibrio cholerae murmurs: A neoteric advancement in cholera research. Indian J Microbiol 55:121–130. doi:10.1007/s12088-015-0520-1
  5. Huma N, Shankar P, Kushwah J, Bhushan A, Joshi J, Mukherjee T, Raju SC, Purohit HJ, Kalia VC (2011) Diversity and polymorphism in AHL-lactonase gene (aiiA) of Bacillus. J Microbiol Biotechnol 21:1001-1011. doi:10.4014/jmb.1105.05056
  6. Kalia VC (2013) Quorum sensing inhibitors: an overview. Biotechnol Adv 31:224–245. doi:10.1016/j.biotechadv.2012.10.004
  7. Kalia VC (2014) In search of versatile organisms for quorum‐sensing inhibitors: acyl homoserine lactones (AHL)‐acylase and AHL‐lactonase. FEMS Microbiology Letters 359:143. doi: 10.1111/1574-6968.12585
  8. Kalia VC (2014) Microbes, antimicrobials and resistance: The battle goes on. Indian J Microbiol 54:1-2. doi: 10.1007/s12088-013-0443-7
  9. Kalia VC (2015) Quorum Sensing vs Quorum Quenching: A Battle with No End in Sight.
  10. Kalia VC (2016) The Battle: Microbes versus vaccines, antibiotics and antipathogens.
  11. Kalia VC (2015) Microbes: The most friendly beings? In: Quorum Sensing vs Quorum Quenching: A Battle with No End in Sight, 1-5. Editor: VC Kalia. Springer India. doi:10.1007/978-81-322-1982-8_1
  12. Kalia VC, Prakash J, Koul S, Ray S (2017) Simple and rapid method for detecting biofilm forming bacteria. Indian J Microbiol 56:109-111. doi: 10.1007/s12088-016-0616-2
  13. Kalia VC, Kumar P, Pandian SK, Sharma P (2014) Biofouling control by quorum quenching. Hb_25 Springer Handbook of Marine Biotechnology Chapter 15:431-440. Springer Ed. S. K. Kim.
  14. Kalia VC, Purohit HJ (2011) Quenching the quorum sensing system: potential antibacterial drug targets. Crit Rev Microbiol 37:121-140. doi: 10.3109/1040841X.2010.532479
  15. Kalia VC, Raju SC, Purohit HJ (2011) Genomic analysis reveals versatile organisms for quorum quenching enzymes: Acyl-homoserine lactone-acylase and –lactonase. Open Microbiol J 5:1-13. doi:10.2174/1874285801105010001
  16. Kalia VC, Ray S, Koul s, Prakash J and Kumar R (2016) Bacillus - Industrial work-horse of the microbial world. Industrial-Work-Horse-of-the-Microbial-World-3675.html
17. Kalia VC, Wood TK, Kumar P (2014) Evolution of resistance to quorum-sensing inhibitors. Microb Ecol 68:13-23. doi:10.1007/s00248-013-0316-y

  1. Kalia VC, Kumar P (2015) Potential applications of quorum sensing inhibitors in diverse fields . In: Quorum Sensing vs Quorum Quenching: A Battle with No End in Sight, 359-370. Editor: VC Kalia. Springer India. doi:10.1007/978-81-322-1982-8_29
  2. Kalia VC, Kumar P (2015) The Battle: Quorum-sensing inhibitors versus evolution of bacterial resistance . In: Quorum Sensing vs Quorum Quenching: A Battle with No End in Sight, 385-391. Editor: VC Kalia. Springer India. doi:10.1007/978-81-322-1982-8_31
  3. Kaur G, Rajesh S, Princy SA (2015) Plausible drug targets in the Streptococcus mutans quorum sensing pathways to combat dental biofilms and associated risks. Indian J Microbiol 55:349-357. doi:10.1007/s12088-015-0534-8
  4. Koul S, Kalia VC (2017) Multiplicity of quorum quenching enzymes: A potential mechanism to limit quorum sensing bacterial population. Indian J Microbiol 56:100-108. doi: 10.1007/s12088-016-0633-1
  5. Koul S, Prakash J, Mishra A, Kalia VC (2016) Potential emergence of multi-quorum sensing inhibitor resistant (MQSIR) bacteria. Indian J Microbiol 56:1-18. doi: 10.1007/s12088-015-0558-0
  6. Kumar P, Koul S, Patel SKS, Lee JK, Kalia VC (2015) Heterologous expression of quorum sensing inhibitory genes in diverse organisms . In: Quorum Sensing vs Quorum Quenching: A Battle with No End in Sight, 343-356. Editor: VC Kalia. Springer India. doi:10.1007/978-81-322-1982-8_28 Kumar P, Patel SKS, Lee JK, Kalia VC (2013) Extending the limits of Bacillus for novel biotechnological applications. Biotechnol Adv 31:1543-1561. doi:10.1016/j.biotechadv.2013.08.007
  7. Moroeanu VI, Vamanu E, Paun G, Neagu E, Ungureanu OR, Eremia SAV, Radu GL, Ionescu R, Pelinescu DR (2015) Probiotic strains influence on infant microbiota in the in vitro colonic fermentation model GIS1. Indian J Microbiol 55:423-429. doi: 10.1007/s12088-015-0542-8
  8. Shang Z, Wang H, Zhou S, Chu W (2014) Characterization of N-acyl-homoserine lactones (AHLs)-deficient clinical isolates of Pseudomonas aeruginosa. Indian J Microbiol 54:158-162. doi: 10.1007/s12088-014-0449-9

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

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