Demystified the Language of Bacterial Resistance

Irin Ann Paul, Yagnit Vadhel and Ann Maria Philip

St. Xavier's College (Autonomous),

Mumbai, Maharashtra, India

 

We all might have heard or read about wars from our class or books. Though we may not know or remember the great wars from history, we all should be well aware of a war that started long ago but that still and will continue - A war for survival. You might wonder what this war is all about. This war is between Bacteria and Antibiotics, called 'Antibiotic resistance'.


Not all bacteria are harmful; a huge number of bacteria reside in our body and are essential for our body. They help in digestion and absorption, provide nutrients, prevent or destroy other disease-causing bacteria that invade our body, and much more. On the other hand, there are harmful bacteria capable of causing various kinds of diseases. These are called 'Pathogenic bacteria' - The real culprits behind many diseases - and the medicines used to treat the infections caused by them are called antibiotics. Antibiotics destroy or slow down the growth of pathogenic bacteria. They are classified as narrow-spectrum or broad-spectrum antibiotics. Broad-spectrum antibiotics are those which are effective against a large number of bacteria, whereas narrow-spectrum antibiotics are the ones that target and work against specific bacteria.


Bacteria are very capable organisms and have various mechanisms to adapt or change themselves such that the antibiotics no longer work against them. In this way, the antibiotics lose their ability to destroy the pathogenic bacteria, and such a condition is called antibiotic resistance. The unnecessary use and overuse of antibiotics have resulted in many bacteria acquiring antibiotic resistance. Some bacteria are resistant to multiple antibiotics and are called multi-resistant organisms (MRO).




Antibiotic resistance is a serious issue. The more bacteria that gain resistance, the more dangerous it is. By avoiding unnecessary prescriptions, following the doctor's prescriptions in the right manner, and by maintaining good hygiene, we could prevent the bacteria from gaining antibiotic resistance. As pathogenic bacteria are progressively gaining resistance against existing antibiotics, the search for new antibiotics is never-ending. Hence, it is necessary to understand the various mechanisms by which bacteria gain resistance. These mechanisms are now being widely studied and researched. One such mechanism is the formation of biofilms.


Biofilms are one of the major reasons for the difficulty in treatment and relapse of clinical bacterial infections. A biofilm is a community of bacteria that mimics multicellular behaviour, covered in an extracellular polymeric matrix. But what is it that makes the organisms in a biofilm antibiotic-resistant? First, the dense matrix reduces the permeability of drugs and acts as a protective barrier against external stresses such as UV, extreme temperature, and pressure. This makes it difficult for us to control the bacteria. Since the environment inside a biofilm is low in nutrients, cell growth slows down. In this state of starvation, bacteria are less sensitive to antibiotics and keep evolving constantly to survive the stressful conditions. As they live in a packed community, the organisms exchange genetic materials with each other and share stress-resistance genes. Bacteria in a biofilm also frequently interact with each other. These interactions, known as ‘quorum sensing’, are crucial for them to gain antimicrobial resistance.


What exactly do we mean by the term quorum sensing? This question might be lingering deep within your brain. Well, the answer is simple - It is the language used by bacteria to communicate. Very different from the tons of languages spoken all over the globe. But can bacteria communicate with each other? Yes, your ears are not hearing something wrong. It is possible, thanks to the specialized biochemicals produced by bacteria, and the genetic, physiological, and anatomical modifications within a bacterial colony. These adaptations have enabled the bacteria to form biofilms, develop resistance against antibiotics, and counter the host immune system.


Now let us dive deeper into the mechanism underlying such an eye-catching and least explored phenomenon of quorum sensing.


Every bacterium possesses a signalling molecule known as an inducer molecule and a receptor on the outer envelope. The inducer molecule is different for gram-negative and gram-positive bacteria. The receptor can be specific to the same or different species of bacteria.




When a bacterium is present in isolation, the concentration of an inducer molecule that it produces is low, making it difficult for it to effectively bind to the receptor. But as the size of the bacterial colony increases with time, the concentration of the inducer molecule also increases. This makes it possible to bind to the receptor either on the same cell or a different cell in the colony of the same or different species of bacteria forming the biofilm. The inducer molecules are usually very small molecules derived from amino acids, formed due to peptide bond formation between different amino acids. They are highly type-specific, meaning that their structure differs from species to species. Generally, gram-negative bacteria have N-acyl homoserine lactones (AHLs), Alkyl quinolones (AQs), and many such identical molecules. In the case of gram-positive bacteria, the signalling molecules are small protein molecules such as the Auto Inducing Peptides (AIPs). When the bacteria are present in a colony, or if a biofilm formation has taken place, the inducer molecules from more than one cell are released. Due to the presence of functional groups such as -NH2, -OH, -COOH, and many such electronegative groups, the inducer molecules form one or more hydrogen bonds with the interior of the receptor containing histidine units, thanks to the presence of highly electronegative groups on the histidine molecule that forms a core of the receptor’s structure. The binding of the inducer molecule to the receptor triggers the activation of a complex biochemical pathway, which in turn leads to gene regulation, stress tolerance and the formation of biofilms by secretion of extracellular polysaccharides.


An interesting fact - this pathway is also responsible for the formation of the enzyme Luciferase in certain bioluminescent bacteria, aka light-producing bacteria. This enzyme is formed in the presence of a protein Luxl and detected by the protein LuxR. The gene luxS plays a key role in regulating quorum sensing. The process of extracellular communication is the same for all bacteria that possess a gene luxS. It is possible only when the bacterial population inside the colony is significantly large enough to allow such an interaction to occur.


In recent times, the rapid advancements in microbiology, molecular biology, biochemistry, and genetics have enabled us to understand the mechanism of quorum sensing. But advanced research in quorum sensing and biofilm formation is necessary to design novel strategies to overcome the problem of antibiotic resistance using this knowledge.


References:

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