Antibiotic resistance occurs when bacteria develop the ability to survive exposure to drugs designed to kill them or stop their growth. This phenomenon is a major global health concern because it makes treating common bacterial infections increasingly difficult. Understanding the precise molecular strategies bacteria use to evade these potent medications is necessary to develop new treatments.
Intrinsic Versus Acquired Resistance
The ability of a bacterium to resist an antibiotic is categorized based on how that resistance arose. Intrinsic resistance is a natural, inherent trait shared by an entire species, independent of previous drug exposure. For example, bacteria without a cell wall are naturally resistant to drugs like penicillin because they lack the specific molecular target. Gram-negative bacteria also exhibit intrinsic resistance due to their outer membrane, which acts as a natural barrier preventing large antibiotic molecules, such as vancomycin, from reaching internal targets.
Acquired resistance, in contrast, develops in a bacterium that was previously susceptible to a drug. This change results from new genetic material being introduced or through spontaneous mutations within the bacterial DNA. A bacterium can acquire this new genetic advantage by absorbing DNA from its environment or by receiving it directly from another bacterium. This allows a previously treatable infection to become difficult to manage.
Blocking Entry and Pumping Drugs Out
Bacteria survive by physically preventing the antibiotic from accumulating inside the cell at a lethal concentration. This is achieved through changes to the cell surface that reduce the drug’s entry. Gram-negative bacteria often limit drug entry by modifying or losing their porin channels, which are the small “doorways” antibiotics use to cross the outer membrane. The loss of these channels effectively locks the drug out of the cell.
Bacteria also employ specialized active transport systems known as efflux pumps to physically remove the drug from the cell. These protein complexes span the bacterial membrane, recognizing and actively pumping various toxic compounds, including antibiotics, out of the cytoplasm. Efflux pumps are often multi-drug resistant, meaning a single pump can expel several different classes of antibiotics. Increased expression of these pumps ensures the drug concentration inside the bacterial cell remains too low to be effective.
Enzymatic Destruction of Antibiotics
A common resistance mechanism involves the use of bacterial enzymes to chemically destroy or modify the antibiotic molecule. This strategy neutralizes the drug’s active chemical structure before it can reach its target inside the cell. The most well-known examples are the beta-lactamase enzymes, which cause resistance to penicillins and cephalosporins. These enzymes hydrolyze the amide bond within the beta-lactam ring, rendering the antibiotic inactive.
Beyond hydrolysis, bacteria use other modifying enzymes to add chemical groups to antibiotics, preventing them from binding to their intended targets. For example, resistance to aminoglycoside antibiotics often involves enzymes that add acetyl, phosphate, or adenyl groups to the drug molecule. This addition changes the drug’s size, structure, and electrical properties, making it unable to fit correctly into the bacterial ribosome.
Altering the Drug’s Target Site
Instead of destroying the drug, bacteria can make structural changes to their internal machinery so the antibiotic can no longer bind effectively. This involves altering the drug’s target site, such as the cell wall synthesis machinery or the ribosome. Resistance to methicillin, for instance, occurs when bacteria acquire the mecA gene, which codes for a new Penicillin-Binding Protein (PBP) called PBP2a. This altered PBP has a very low affinity for beta-lactam antibiotics, allowing the bacterium to continue building its cell wall even in the drug’s presence.
Similarly, bacteria can alter the ribosomal subunits to resist drugs that inhibit protein synthesis, such as macrolides and tetracyclines. This modification involves mutations in the ribosomal RNA or the enzymatic addition of chemical tags, like a methyl group, to the ribosome structure. Even a subtle change in the ribosome’s shape can prevent the antibiotic from binding. Resistance to vancomycin also involves target modification, where the bacteria change the structure of the peptidoglycan precursors in the cell wall, which reduces the drug’s binding ability.
Horizontal Transfer of Resistance Genes
The rapid global spread of antibiotic resistance is primarily driven by the ability of bacteria to share resistance genes, a process called Horizontal Gene Transfer (HGT). This gene sharing allows a susceptible bacterium to quickly acquire defense mechanisms, such as efflux pumps or drug-destroying enzymes, from a resistant neighbor. The resistance genes are often located on mobile genetic elements, such as plasmids, which are small, circular pieces of DNA separate from the main chromosome.
One of the most common methods of HGT is conjugation, which involves direct cell-to-cell contact. During conjugation, a bacterium extends a tube-like structure to another cell and transfers the resistance-carrying plasmid through it. Resistance genes can also be transferred through transformation, where a bacterium takes up naked DNA fragments released into the environment from dead bacteria. Finally, transduction involves bacteriophages, which are viruses that infect bacteria, accidentally transferring bacterial DNA, including resistance genes, from one host cell to another.