An Alternative to Antibiotics

I lay dormant. I quietly absorb nutrients from my environment, growing, growing, growing — and then I split into two. This happens over and over again, until there are millions of me and my senses tingle. It is time. We gather our forces and attack the host. I am a single bacterium in a human, and the senses I speak of are my receptors being triggered.

Bacteria help us digest food, make vitamins, and educate our immune system against bad microbes; however, they also cause widespread disease. Yet, bacteria are single-celled, microscopic organisms that are relatively innocuous on their own — so how do they do it?

Bacteria naturally secrete small molecules called autoinducers (AIs). These allow bacteria to measure the surrounding population density, and get a sense of how many other bacteria are around. With a single bacterium, the AI molecules released into the environment will just float away. When the population grows, however, the concentration of autoinducers will increase accordingly, plugging into receptors on the surface of other bacteria. Once a threshold level has been reached, certain group-behavior genes become activated. Whether these genes influence secretion of toxins, bioluminescence, or production of sticky extracellular substances to form biofilm, these behaviors are geared towards bettering the bacteria’s chances of survival by providing the population with superior access to nutrients. This chemical signaling process, called quorum sensing (QS), enables coordination of gene expression as a function of local population density.

Enlarge

Quorum_Sensing
Quorum sensing activates group behavior when there are enough bacteria present.

Quorum sensing is a powerful tool for bacteria, but it comes at the cost of our health and safety. Complex microbial communities called biofilms are resistant to conventional methods of eradicating microbes, and cost the world economy billions of dollars in regard to equipment damage, product contamination, energy losses, and infections. Biofilms are up to a thousand times more resistant to antibiotics than free-floating bacteria, which is due to both resistant mutants and the presence of drug-tolerant persister cells, a subpopulation that remains after the initial period of rapid cell death with antibiotics. These biofilms form on medical equipment, clogging stents and catheters, and are the primary cause of delayed healing and infection in chronic wounds, especially surgical ones. Thus, even while antibiotics may exhibit initial success in treating biofilm infections, these infections often translate into numerous chronic diseases due to their resilient presence in the human body.

Furthermore, bacteria utilize quorum sensing in launching attacks against hosts. When bacteria enter the body and quietly begin to replicate, the host is initially unaware of their presence. It isn’t until there is a sufficiently high concentration of autoinducers that the bacteria begin expressing virulence factors. Thus, there is much to be gained in learning about the specific quorum-sensing mechanisms of clinically-relevant bacteria. Emerging research on the QS circuits of P. aeruginosa and S. aureus, which cause persistent diseases, and V. cholerae and B. cereus, which cause acute infections, is just the beginning of a novel approach towards antimicrobial treatments.

What if we could somehow disrupt quorum sensing? It might be difficult to stop the production of autoinducers, but what if we could stop the detection of these molecules? Dr. Bonnie Bassler and her team at Princeton University have synthesized small molecules that plug into P. aeruginosa’s autoinducer receptors but do not “function” or lead to the expression of collective group behaviors. The molecule successfully prevents virulence factor expression and biofilm formation in vitro and in vivo, showing promise for further development of small-molecule modulators of quorum sensing. Dr. Bassler’s work has shown that we can create drugs that jam bacterial communication so that their coordinated attack is never triggered, buying time for the immune system to react to the invaders. The main advantage of such drugs would be in treating antibiotic-resistant infections, because quorum sensing inhibitors do not impose the harsh selective pressures that develop antibiotic resistance.

Dr. Bassler’s work has shown that we can create drugs that jam bacterial communication so that their coordinated attack is never triggered, buying time for the immune system to react to the invaders.

Bacteria, however, don’t live by themselves. They live in incredibly diverse mixtures, with thousands of other species occupying one area at the same time. Thus, we can’t consider one species at a time — we have to look at the big picture. It turns out that bacteria have, in addition to their species-specific network, a generic communication system that allows them to discern who their neighbors are and direct each participant in the community to maximize efficiency. Researchers believe we can create a broad-spectrum QS inhibitor that can counteract the menagerie of bacteria colonizing prosthetics, stents, and other medical equipment without running the risk of developing resistant strains. The next step forward would be research how bacteria react in more realistic environments, with multiple other species. There may be an entire class of valuable molecules that have yet to be discovered.

Deciphering the secret language of bacteria is now more important than ever. With antibiotic resistance on the rise, utilizing small molecules to disable quorum sensing is a path that promises an innovative therapeutic method. Of course, there is still a ways to go before these small molecules can become a commonplace treatment in the medical industry. But winning this battle — cracking the four-billion-year-old code and understanding the Enigma — may help us win the war.

About The Author