Quorum sensing: An evolving field

Antimicrobial resistance was one of the top ten global health threats in 2021, and it grows worse with new pathogen strains every year [1]. While reducing antimicrobial resistance is a global priority, therapies for existing infections still need to be found.

Biofilms and you

We typically think of bacteria as free organisms drifting along in their environments. If this were the case, it would be much easier to deal with them. Instead, bacteria can form biofilms–masses of bacteria that bond to a surface and cannot be easily removed by existing antibiotics.

A biofilm has an extracellular matrix (ECM) that houses the bacteria, provides protection, and supports the growing colonies [2]. The danger in these biofilms lies in their resilience. Not only does the ECM protect against their physical removal, but it also provides them with antibiotic resistance by delaying substance penetration and thus quenching antibiotic effects.

Biofilms may house multiple bacterial species, and these heterogenous bacterial populations can also render antibiotics ineffective [3]. Killing the organisms in the ECM is not enough to get rid of biofilms [4]. Furthermore, the rate of horizontal gene transfer–the nonsexual transfer of genetic material between organisms–in biofilms is much higher than in free-floating organisms, allowing resistant plasmids to spread [2].

The human cost

Our own immune systems have difficulty dealing with biofilms. Inflammation, one of the body’s natural methods to deal with infection, facilitates the adhesion of biofilms. In some cases, biofilms also attach to the host’s very tissue [5]. Biofilms contribute to 80% of chronic and recurring infections in humans, severely lowering people’s quality of life [6].

These infections also disproportionately affect those with weaker immune systems. Worse, these biofilms usually grow on lifesaving medical devices such as medical implants, venous catheters, and prostheses [2].

The detrimental effects of biofilms extend even beyond the medical field. Biofilms can affect drinking water systems by forming in pipelines, thereby causing corrosion and infectious bacteria spread. They can also affect food safety by forming on food processing machines and on food itself [7].

Quorum sensing and its contribution to biofilm formation

Biofilms form as a result of different mechanisms, one of which is quorum sensing. Quorum sensing (QS) is a form of communication between cells, allowing communities of bacteria to share information about cell density and adjust gene expression accordingly. QS uses signal molecules called autoinducers and helps regulate factors that require synchronous movements such as the expression of virulence factors that promote infection and the formation of biofilm [8]. QS also regulates the biofilm dispersion, or the release of bacteria from the biofilm in order to form new colonies [9].

Since QS is instrumental to the formation of biofilm, quorum sensing inhibition and quorum quenching have been utilized for novel therapies against biofilms [4]. QS inhibitors are applied, sometimes topically, to biofilms. These can target the production of autoinducers, the autoinducer molecules themselves, or the sites to which autoinducers bind. These methods are not vulnerable to the antimicrobial resistance of established biofilm. Neither do they cause evolutionary pressure to select for resistance since they only target the molecules involved in bacterial communication, and not the bacterial cells directly [10].

Other methods against biofilms include combinations of antibiotics, physical removal, synthetic antibodies, ultrasonic therapy, photodynamic therapy, and antimicrobial surface coatings [4]. Some, particularly those using antibiotics, are aggressive treatments that require many resources [3][4]. QS inhibition is synergistic with these treatments, but may also provide alternative avenues that do not build antimicrobial resistance in surviving cells. Furthermore, QS inhibition can also target virulence factors, which make bacteria more dangerous to humans.

The rise in interest in targeting QS inhibition mostly started in the 2000s, with several start-ups being established for the development of drugs for QS inhibition [10]. These attempted to control the virulence factors and communication of the target organisms, limiting their pathogenicity [11].

Difficulties in QS therapy

As of 2017, a wealth of research on QS had been accumulated. The research focused on the individual elements of QS such as the targeting mechanism and the molecules used, the species that usually make use of it, and the mechanism itself [12]. However, there is a notable decline in QS research in the years after, partly due to the limitations of targeting quorum sensing.

Just like in drug discovery, limitations such as reduced effectivity in animal models and toxicity also apply to QS. However, since QS inhibition is unlike antibiotic treatment, there are less straightforward questions about the application of QS inhibitors to be answered. For example, QS inhibitors may find use as either a prophylactic or a curative, but it is still unknown which is more effective [12].

In vivo studies are scarce, particularly in more serious internal infections. Inhibiting QS has variable effects on the growth of biofilm in some bacterial species, so its effect on virulence cannot be clearly established [13]. The virulence of certain bacteria can even be increased by QS inhibition [14].

Furthermore, QS inhibitors are usually specific to certain bacterial species, limiting the effectivity of these drugs. Inhibitors may also be carried away from the biofilm or bacteria may also start to develop resistance against QS inhibition [3][14]. QS inhibitors also target specific molecules produced by bacteria, and these may interfere with the same molecules produced by beneficial bacteria such as the gut microbiome [14].

Overcoming challenges

Even with these limitations, research on quorum sensing continues to push on.

Combination of different therapies seems to be most effective, since QS inhibition does not, by itself, remove infection. Some research focuses on natural QS inhibitors, which combine antibiotic properties with QS inhibition. Yet, others aim to discover QS inhibition properties in already-used drugs and compounds [15].

Another study explores the idea of using a microalgae-based hydrogel with natural QS inhibitors to promote wound healing, especially important to diabetic patients. Using both in vitro and in vivo assays, a variety of therapies were combined into the gel in order to promote wound healing and alleviate associated factors such as hypoxia and biofilm formation. This approach also solves one of the earlier problems with QS inhibition, namely its short retention time and weak antibacterial effect [16].

Despite the difficulties with QS research, innovation still flourishes. While the field boasts many challenges, false starts, and complications, there is no study that did not contribute to the progress that was made. This is the perfect example of the contribution of scientific research, and the messy but rewarding path to progress.

References

[1] World Health Organization. (2017, November 17). Antimicrobial resistance. World Health Organization. Retrieved April 6, 2022, from https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

[2] Donlan, R. M. (2001). Biofilm Formation: A clinically relevant microbiological process. Clinical Infectious Diseases, 33(8), 1387–1392. https://doi.org/10.1086/322972

[3] Harriott, M. M. (2019). Biofilms and antibiotics. Reference Module in Biomedical Sciences. https://doi.org/10.1016/b978-0-12-801238-3.62124-4

[4] Koo, H., Allan, R. N., Howlin, R. P., Stoodley, P., & Hall-Stoodley, L. (2017). Targeting microbial biofilms: Current and prospective therapeutic strategies. Nature Reviews Microbiology, 15(12), 740–755. https://doi.org/10.1038/nrmicro.2017.99

[5] Srivastava, S., & Bhargava, A. (2015). Biofilms and human health. Biotechnology Letters, 38(1), 1–22. https://doi.org/10.1007/s10529-015-1960-8

[6] Sharma, D., Misba, L., & Khan, A. U. (2019). Antibiotics versus biofilm: An emerging battleground in Microbial Communities. Antimicrobial Resistance & Infection Control, 8(1). https://doi.org/10.1186/s13756-019-0533-3

[7] Muhammad, M. H., Idris, A. L., Fan, X., Guo, Y., Yu, Y., Jin, X., Qiu, J., Guan, X., & Huang, T. (2020). Beyond risk: Bacterial biofilms and their regulating approaches. Frontiers in Microbiology, 11. https://doi.org/10.3389/fmicb.2020.00928

[8] 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). https://doi.org/10.1101/cshperspect.a012427

[9] Solano, C., Echeverz, M., & Lasa, I. (2014). Biofilm dispersion and quorum sensing. Current Opinion in Microbiology, 18, 96–104. https://doi.org/10.1016/j.mib.2014.02.008

[10] Hentzer, M., & Givskov, M. (2003). Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. Journal of Clinical Investigation, 112(9), 1300–1307. https://doi.org/10.1172/jci20074

[11] Chen, F., Gao, Y., Chen, X., Yu, Z., & Li, X. (2013). Quorum quenching enzymes and their application in degrading signal molecules to block quorum sensing-dependent infection. International Journal of Molecular Sciences, 14(9), 17477–17500. https://doi.org/10.3390/ijms140917477

[12] Whiteley, M., Diggle, S. P., & Greenberg, E. P. (2017). Progress in and promise of Bacterial Quorum Sensing Research. Nature, 551(7680), 313–320. https://doi.org/10.1038/nature24624

[13] Piewngam, P., Chiou, J., Chatterjee, P., & Otto, M. (2020). Alternative approaches to treat bacterial infections: Targeting quorum-sensing. Expert Review of Anti-Infective Therapy, 18(6), 499–510. https://doi.org/10.1080/14787210.2020.1750951

[14] Krzyżek, P. (2019). Challenges and limitations of anti-quorum sensing therapies. Frontiers in Microbiology, 10. https://doi.org/10.3389/fmicb.2019.02473

[15] Bouyahya, A., Chamkhi, I., Balahbib, A., Rebezov, M., Shariati, M. A., Wilairatana, P., Mubarak, M. S., Benali, T., & El Omari, N. (2022). Mechanisms, anti-quorum-sensing actions, and clinical trials of medicinal plant bioactive compounds against bacteria: A comprehensive review. Molecules, 27(5), 1484. https://doi.org/10.3390/molecules27051484

[16] Hu, H., Zhong, D., Li, W., Lin, X., He, J., Sun, Y., Wu, Y., Shi, M., Chen, X., Xu, F., & Zhou, M. (2022). Microalgae-based bioactive hydrogel loaded with quorum sensing inhibitor promotes infected wound healing. Nano Today, 42, 101368. https://doi.org/10.1016/j.nantod.2021.101368

Written by Nia Manlulu
Proofread by Sophia Abulencia, Megan Gozum, and Rhaena Pablo
Art by Bianca Ochave

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The official publication of the University of the Philippines Molecular Biology and Biotechnology Society.

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