Molecular mechanisms of antibiotic resistance

The number of infections caused by multidrug-resistant bacteria is increasing globally, and the specter of untreatable infections is becoming a reality. The most recent World Economic Forum Global Risks reports have listed anti-biotic resistance as one of the greatest threats to human health 1–3. It is estimated that in Europe 25,000 people die each year as a result of multidrug-resistant bacterial infections and this costs the European Union economy €1.5 billion annually. Bacteria can be intrinsically resistant to certain antibiotics, but can also acquire resistance to antibiotics via mutations in chromosomal genes and by horizontal gene transfer. The simplest example of intrinsic, resistance in an individual species results from the absence of a susceptible target of a specific antibiotic. In addition to intrinsic resistance, bacteria can acquire or develop resistance to antibiotics. This can be mediated by several mechanisms. Main groups: First, those that minimize the intracellular concentrations of the antibiotic as a result of poor penetration into the bacterium or of antibiotic efflux; Second, those that modify the antibiotic target by genetic mutation or post-translational modification of the target; Third, those that inactivate the antibiotic by hydrolysis or modification. Prevention of access to the target. Reduced permeability: Compared with Gram-positive species, Gram-negative bacteria are intrinsically less permeable to many antibiotics as their outer membrane forms a permeability barrier. Increased efflux: Bacterial efflux pumps actively transport many antibiotics out of the cell and are major contributors to the intrinsic resistance of Gram-negative bacteria to many of the drugs that can be used to treat Gram-positive bacterial infections. Changes in antibiotic targets by mutation: Most antibiotics specifically bind to their targets with high affinity, thus preventing the normal activity of the target. Changes to the target structure that prevent efficient antibiotic binding, but that still enable the target to carry out its normal function, can confer resistance. Modification (and protection) of targets: Protection by modification of the target can also be an effective means of antibiotic resistance that does not require a mutational change in the genes encoding the target molecules. Direct modification of antibiotics: Inactivation of antibiotics by hydrolysis: The enzyme catalyzed modification of antibiotics is a major mechanism of antibiotic resistance that has been relevant since the first use of antibiotics, with the discovery of penicillinase (a β-lactamase), in 1940. Inactivation of antibiotic by transfer of a chemical group: The addition of chemical groups to vulnerable sites on the antibiotic molecule by bacterial enzymes causes antibiotic resistance by preventing the antibiotic from binding to its target protein as a result of steric hindrance.

کلیدواژه ها:

Molecular mechanism ، Antibiotic resistance ، Infection