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Controlling Pathogens: Using the Divide and Conquer Strategy
#1
Unity is strength, they say.

This is also true in bacterial pathogenesis. Recent researches reveal that many pathogenic bacteria have communication networks that let them know when their numbers are sufficient to overwhelm host defenses. The theory is simple: if they began the assault with an army too small, the host can easily kill them. But if there are enough fighters, they can defeat the host. Their strategy is to multiply within the host without causing damage, until a sufficient cell number is reached. When the population is adequate to overcome host defense systems, they become violent.

So, how do these single celled creatures actually ‘talk’ with each other?

It is found that bacterial cell-to-cell communication occurs via low molecular weight diffusible organic molecules referred to as autoinducers (AIs). These AIs diffuse away at low cell densities and, therefore, are present at concentrations below the level required for detection. With the cell density, increases the concentrations of AIs. Upon reaching a critical concentration, the AIs bind to and stimulate receptors inside bacterial cells. These receptors then activate the transcription of genes necessary for bacterial virulence, such as the genes regulating the production of virulence factors, formation of biofilms, antibiotic resistance etc. This process is known as autoinduction. Since this process is activated after a critical population density, or quorum, is reached, it is also termed as Quorum Sensing (QS).

Different bacterial species use different languages, i.e. different classes of signalling molecules. Furthermore, single bacterial species may have more than one QS system and therefore can use more than one signal molecule. Gram negative bacteria primarily use acyl-homoserine lactones (AHLs) as their signalling molecules while Gram-positive bacteria use peptides, called autoinducing peptides (AIPs). Some groups of AIs are known to function as interspecies and interkingdom communication networks.

Many clinically-important bacteria use QS to regulate their virulence.

Therefore, scientists have been studying in detail, the role of quorum sensing in the virulence of many human pathogens. QS is found to regulate genes involved in virulence, biofilm architecture and antibiotic resistance in these bacteria, thus playing a vital role during the infections by these pathogens.

One such culprit is Staphylococcus aureus, a member of the normal flora, which can be a dangerous opportunistic pathogen causing infections leading to pneumonia, bacteremia, and sepsis. Moreover, they form biofilms on clinical surfaces, thus accounting for many hospital related infections. S. aureus infections are difficult to eliminate due to their resistance to many antibiotics.

Pseudomonas aerogenosa is another opportunistic pathogen which produces both acute and chronic diseases in humans. It is responsible for severe respiratory infections such as chronic lung infection in cystic fibrosis patients. P. aerogenosa is also associated with nosocomial infections. They have the ability of forming complex biofilms which are highly resistant to antibiotics.

The role of quorum sensing in the virulence of Escherichia coli has also been demonstrated. QS controls the expression of genes regulating the functions such as flagellar motility, surface adhesion and Shiga toxin production which are involved in the pathogenicity of Enterohaemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC).

Among other pathogenic bacteria that employ QS in their virulence are Bacillus cereus, Salmonella typhimurium and Vibrio cholerae.

Keep them in the dark.

And you can control them, scientists suggest. The idea is to block their communication systems and keep the bacteria from knowing that the optimal population density has reached. This will prevent the transition from inert mode to the virulent mode.

The researchers believe that this strategy would not cause antibiotic resistance in bacteria because it doesn’t aim to kill the cells. When a community of bacteria is treated with traditional antibiotics, a few resistant mutants within the population will survive. Proliferation and further mutation of these survivors will result in antibiotic resistant populations. On the contrary, blocking their QS system will merely keep them in a non-aggressive form, thus allowing the immune system of the body to combat the bacteria.

Quorum Sensing Inhibitors: the new wonder drug?

One of the most successful mechanisms of blocking QS is through competitive inhibitors which are structural analogues of the primary autoinducers produced by bacteria. These inhibitors bind to the regulatory regions of the virulent genes, thereby preventing the binding of bacterial AIs. This inhibits the activation those genes, thus disabling the expression of virulence and giving enough time for the host defense system to combat bacteria.

Efforts have been made to discover such inhibitors with the goal of designing novel antimicrobial therapeutics. Natural quorum sensing inhibitors identified thus far include cyclic sulphur compounds, halogenated furanones, patulin and penicillin acid. Garlic extract was also considered to be a potential QS inhibitor.

Scientists report based on in-vitro studies, that bacteria do not seem to develop resistance to these inhibitors. In one study, when V. cholerae bacteria were grown in the presence of a large excess of such inhibitors, resistance could not be observed even after 26 subsequent generations.

There is hope that this could be the new wonder drug for conquering antibiotic resistant infections.


For further reference:
  • Antunes, L.C.M., Ferreira, R.B. R., Buckner, M.M. C., Finlay, B.B. (2010) Quorum sensing in bacterial virulence, Microbiology,156, 2271–2282.
  • Rutherford, S. T., Bassler, B. L. (2012). Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control. Cold Spring Harbor perspectives in medicine, 2(11).
  • Reading, N. C., & Sperandio, V. (2006). Quorum sensing: the many languages of bacteria. FEMS microbiology letters, 254(1), 1-11.
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Controlling Pathogens: Using the Divide and Conquer Strategy00