When Medicines Fail: The Science Behind Antimicrobial Resistance

Antimicrobial resistance (AMR) is a growing global health crisis that threatens our ability to treat common infections and perform routine medical procedures. While AMR occurs naturally, as bacteria evolve to develop defense mechanisms against antibiotics, the misuse and overuse of these drugs have increased AMR at an unprecedented rate, rendering some of our most universal medicines ineffective.

Genetic Mutations

At the heart of AMR lies the genetic mutations of microorganisms. Bacteria, for instance, possess an astonishing ability to adapt and evolve. When exposed to antimicrobial agents, they can develop a variety of mutations that serve as defense mechanisms against these drugs and eventually transmit these resistant traits to subsequent generations. Bacteria can even accumulate multiple mutations or acquire multiple resistance genes, making them highly resistant to multiple antibiotics.

Target modification

One common mechanism of resistance involves modifying the target site of the drug. For example, bacteria often acquire point mutations in the genes that code for ribosomal proteins or RNA, which are the target sites for antibiotics like tetracyclines or macrolides. These mutations can alter the structure of the target, making it less susceptible to binding by the antibiotic.

Efflux pump overexpression

Bacteria can also develop resistance by overexpressing efflux pumps, which are proteins that actively pump out antibiotics from the bacterial cell before they can exert their effects. Mutations in the regulatory genes controlling these pumps can lead to increased expression, increasing the removal of antibiotics from the cell.

Enzyme modification

Some antibiotics are inactivated or destroyed by enzymes. Bacteria can acquire mutations that enhance the production of enzymes that break down antibiotic molecules, such as β-lactamase enzymes that hydrolyze beta-lactam antibiotics like penicillin, rendering them inactive.

Altered cell wall

Bacterial cell walls play a crucial role in protecting the cell from external threats, including antibiotics. Mutations in genes responsible for cell wall synthesis can lead to changes in cell wall structure, making it less permeable to certain antibiotics. This resistance mechanism is common in Gram-negative bacteria, such as Klebsiella pneumoniae and Neisseria gonorrhoeae.

Selection Pressure

Selection pressure refers to the influence or force exerted by the environment on a population of organisms, driving changes in the population's genetic composition over time. When microorganisms are exposed to antimicrobial agents, selective pressures favour the survival of resistant pathogens, eventually leading to the development of entire resistant populations and strains.

When antibiotics are used to treat infections, they target and kill susceptible bacteria while leaving behind any bacteria with natural or acquired resistance. These resistant bacteria have genetic mutations or mechanisms that allow them to survive the antibiotic onslaught. Then, in the absence of antibiotics, the resistant bacteria have a survival advantage and reproduce and proliferate in the host's body, causing the infection to persist or worsen. Following the principle of natural selection, the resistant bacteria are more likely to survive and pass their resistance traits onto their offspring. The continued use of antibiotics, especially when used inappropriately or unnecessarily, exerts even more selective pressure, leading to the development of additional resistance mechanisms that create bacteria resilient to multiple types of antibiotics.

Horizontal Gene Transfer

Horizontal gene transfer (HGT) is the process in which genetic material, often in the form of genes or plasmids, is transferred between different microorganisms. Unlike vertical gene transfer, which occurs from parents to offspring during reproduction, HGT allows for the rapid sharing of genetic information among microorganisms, including bacteria. Common modes of HGT in bacteria include conjugation (direct cell-to-cell contact), transformation (uptake of naked DNA from the environment), and transduction (transfer of genetic material via bacteriophages or viruses).

HGT plays a significant role in the development of AMR, as antibiotic-resistant bacteria can transfer resistant genes to surrounding bacteria, making them resistant to the same or similar antibiotics. This accelerated acquisition of resistance genes enables bacteria to become resistant to antibiotics more quickly than through mutation alone, as they can bypass the relatively slow process of natural selection. HGT can also lead to the accumulation of multiple resistance genes within a single bacterium, resulting in multi-drug resistant strains. These strains are particularly challenging to treat, as few effective antibiotics remain for combating infections caused by these bacteria.

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