Since the discovery of antibiotics, the number of deaths attributed to infectious diseases has declined by 70%. However, microorganisms have developed a plethora of mechanism against any antibiotic exposure, and development of resistance to a single antibiotic is today deemed inevitable. In addition to acquired resistance, many microorganisms are intrinsically resistant to many of the antibiotics nowadays employed. As a result, each year antibiotic-resistant pathogens cause at least 700,000 deaths worldwide. Driven by factors such as misuse and overuse, WHO has indeed classified antimicrobial resistance as one of the top 10 global health threats faced by mankind. Despite decades of worsening figures, there has been a well-documented decrease in new antibiotics in the discovery pipeline, particularly of first-in-class antibiotics that target novel bacterial processes. In fact, since the identification of penicillin in 1928, there have been only a few physiological processes targeted by antibiotics, and newly approved antibiotics are often improved versions.
Incidentally, when the mechanisms of action of the main antibiotics were identified, it was believed that, since the targets represented only in bacteria, the use of antibiotics would be free from any side effects. But this was not the case and everyone knows that the prolonged use of antibiotics has side effects affecting organs such as the liver, kidneys, intestines and other areas. For example, it was the use of aminoglycosides that revealed their previously unknown toxicity on kidney function and the hearing system. For penicillins and cephalosporins, toxic effects on the skin, intestines, liver and also on the lungs began to signal. The side effects of tetracyclines were not fully justified as the point of action (a step in protein synthesis that is different from the human one in bacteria) was considered to be the exclusive prerogative of microorganisms. Until it was discovered that tetracyclines can interact with numerous enzymes in animal and human cells. Not to mention sulfonamides and their bone marrow toxicity; today it is known that it depends on the interference with signaling pathways necessary for staminal maturation.
To address the urgent need for new antibiotics, researchers have turned to screening libraries of diverse natural and synthetic molecules. In biochemical screening, molecules are tested for activity against a validated bacterial target, such as an essential protein, so the target is well established prior to the screen being conducted. However, there has been a recent shift to phenotypic-based screening, where a parameter of cellular function is measured in response to screening molecules. Phenotypic-based screens have uncovered promising antimicrobial agents, but a key hurdle for advancing these molecules in the development pipeline is this task of elucidating the molecular mechanisms of action responsible for their activity. Also important for validating their use as therapeutics is determining whether antimicrobial agents target processes unrelated to their antimicrobial activity. Therefore, it is critical to have sound methodologies for understanding both the molecular targets and mechanisms of action of new antimicrobial agents.
Understanding an antibiotics’ mechanism of action is useful for its development beyond discovery. Clinical trials take time, are either cumbersome and expensive and possible failures are possible. For example, a mechanistic insight can help predict the spectrum of activity across microorganisms. This information can also be used to strategically derivatize molecules to lessen host toxicity, increase affinity or promote uptake. Methodologies for characterizing mechanisms of action today may include biochemical and genetic approaches. These latter, such as selecting and screening for resistance, are also widely used, and with the advent of RNA sequencing, transcriptome changes can be monitored to identify global expression patterns. Genomics, proteomics and other “omics” biotechs are now available, therefore there is only a need for committment. Since the infectious threats are constant and the competent authorities deem that the battle will never be over, more knowedge and cooperation among scientists will be essential.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
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Martin JK, Sheehan JP et al. Cell 2020; 181:1518–1532.
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