All living organisms, including the micro-organisms, have a remarkable ability to follow or develop mechanisms which would ensure their survival in a given environmental condition. In addition, all of them employ their own defense mechanism, against the factors or agents, which might threat their very existence. The global threat of Anti-Microbial Resistance (AMR) is one of the many outcomes of this survival instinct of the bacteria. For establishing an infection, the bacteria have to take care of two things from the very beginning; First, to grow, multiply and colonize the target / host tissue and second, to deploy its defense mechanisms wisely and effectively, such that the effect of any of the agents, which might threat their very existence, could be nullified. Bacteria can use one or multiple mechanisms at the same time to ensure its survival against adverse conditions, in this case, antibiotic stress. The factors which contribute to this entire machinery are either physiological barriers or are genes encoded in the bacterial chromosome or plasmid. The bacterial defense mechanisms implement one or more of the following ways to ensure the protection of bacteria from antibiotics:
Permeability Barrier: This is the first level of defense by the bacteria. For most of the Gram Negative bacteria (like Escherichia coli, Klebsiella pneumoniae), the outer membrane (OM) is a layer that is impervious to most of the commonly used antibiotics. In addition, the aqueous channels called as Porins, which allows the entry of hydrophilic molecules, including antibiotics, across the OM, are also reduced as a measure to restrict the entry of antibiotics inside the bacterial cell. Similar kind of permeability barrier, the thick cell wall (Peptidoglycan; PG) also exists in many Gram Positive bacteria (like Staphylococcus aureus), which, although to a lesser extent, in Gram Positive organisms does a similar job. Some other permeability barriers include the presence of capsule, slime layers or coating with other impermeable substances.
Efflux pumps: The efflux pumps are one of the major contributors to AMR. Their main role could be explained as a set of pumps; whose main role is to expel the drug out of the cell. Bacterial systems usually consist of more than one class of these efflux pumps, each of them, having a specificity to one or other class of antibiotics. Although the most prevalent family of these efflux pumps are the RND family (Resistance Nodulation and Division), there are several other families (like MATE, MDR, SME, ABC etc.) of efflux pumps which serve this purpose
Drug Alteration / Degradation: Some of the bacterial species produces proteins which have the ability to modify or degrade and inactivate one or more class of antibiotics, making them resistant. One of the best example in this area is the role of beta-lactamase, an enzyme produced by the resistant bacteria which can degrade the beta-lactam ring in antibiotics like penicillins, cephalosporins, monobactams, and carbapenems, thereby inactivating them completely.
Target alteration/ modification: An alternate mechanism of evading the effect of antibiotics is target alteration. Generally, antibiotics exert their effect by binding to an essential target or interfering with a metabolic pathway, whose end product is crucial for cell survival. But what if the cell modifies the target? What if the drug is no longer able to recognize its binding site? The answer is simple…. Resistance! Most of the resistance acquired by this method involves one or more mutations in genes encoding the targets. A similar type of resistance is seen in mutants of Staphylococcus aureus against the beta lactam antibiotics, which inhibit the cell wall synthesis. The mutations in their target Penicillin Binding Proteins (PBP’s), confers resistance, by decreasing the affinity of the antibiotic towards its targets.
Biofilm Formation: This method of survival is more of a concerted effort of a bacterial population, instead of a single bacterium. The bacterial population encapsulates itself in a heterogeneous and complex meshwork of exopolysaccharides, proteins, cellular components. The cells thriving in biofilm mode tend to remain adhered to solid surfaces or host tissues and this sheath provides protection against a wide variety of environmental stress conditions, including Antibiotics. The thick layer of biofilm prevents the entry and access of the drugs to the live cells, thereby protecting them.
Thus, in order to win the battle against superbugs and before we prepare ourselves for the battle against the global threat of AMR, it is important to understand the defense strategy of the enemy, in this case, the bacteria. The better the understanding, the better the prevention and cure!