- Antibiotic resistance is a growing global health threat that compromises the effective treatment of bacterial infections.
- Bacteria have evolved various mechanisms to evade the effects of antibiotics, either through intrinsic traits or acquired changes via mutation or horizontal gene transfer. These resistance strategies enable bacteria to survive, proliferate, and spread even in the presence of antimicrobial agents that would normally inhibit or kill them.
- One of the most common resistance mechanisms is the enzymatic inactivation of antibiotics. Bacteria can produce enzymes such as β-lactamases, which hydrolyze the β-lactam ring found in penicillins, cephalosporins, and related antibiotics, rendering them ineffective. Some of these enzymes, like extended-spectrum β-lactamases (ESBLs) and carbapenemases (e.g., KPC, NDM), have evolved to target a broader range of antibiotics. Similarly, aminoglycoside-modifying enzymes chemically alter aminoglycoside antibiotics through acetylation, phosphorylation, or adenylation, reducing their binding affinity for bacterial ribosomes.
- Another key resistance strategy involves alteration of the antibiotic’s target site. Bacteria may acquire mutations or modify proteins to prevent effective drug binding. For example, methicillin-resistant Staphylococcus aureus (MRSA) expresses an altered penicillin-binding protein (PBP2a) with low affinity for β-lactam antibiotics. Likewise, mutations in DNA gyrase or topoisomerase IV confer resistance to fluoroquinolones, and methylation of 23S rRNA (via erm genes) prevents macrolides from binding to the bacterial ribosome.
- Efflux pumps are another important mechanism by which bacteria resist antibiotics. These membrane proteins actively transport antibiotics out of the cell, lowering the intracellular drug concentration. Some pumps are specific to one class of drugs, while others can expel a broad range of antibiotics, contributing to multidrug resistance. For instance, the AcrAB-TolC efflux system in Escherichia coli and MexAB-OprM in Pseudomonas aeruginosa play major roles in resistance to multiple antibiotics, including tetracyclines, chloramphenicol, and fluoroquinolones.
- In Gram-negative bacteria, reduced permeability also plays a role in resistance. These bacteria possess an outer membrane that acts as a barrier to many drugs. Modifications or loss of porin proteins can significantly decrease antibiotic uptake. For example, the loss of OprD porin in P. aeruginosa reduces susceptibility to carbapenems, even in the absence of other resistance mechanisms.
- Bacteria can also develop resistance by bypassing metabolic pathways targeted by antibiotics. This occurs when bacteria produce alternative enzymes or pathways that are not affected by the drug. An example is resistance to trimethoprim-sulfamethoxazole, where resistant strains synthesize a drug-insensitive form of dihydrofolate reductase. Another case is vancomycin resistance in enterococci (VRE), where bacteria alter the terminal amino acids of their cell wall precursors from D-Ala-D-Ala to D-Ala-D-Lac, significantly reducing vancomycin binding affinity.
- Lastly, biofilm formation is a physical and physiological resistance mechanism. Bacteria in biofilms are embedded in a dense extracellular matrix that limits antibiotic penetration and creates a microenvironment that slows bacterial growth, making them less susceptible to many antibiotics. Biofilm-associated resistance is particularly problematic in chronic infections and those involving medical devices, such as catheters or prosthetic implants.
