Antimicrobial Resistance. How Do Antibacterial Agents Work?

Infectious diseases have shaped human history for centuries. For example, the plague pandemic of the 13th century, which spread throughout Europe and the Middle East to the far corners of the globe, claimed approximately 25% of the world’s population. Infectious dysentery ravaged Napoleon’s armies, and tuberculosis, also known as ‘the white plague,’ condemned many of history’s most influential leaders, writers, artists, and scientists to early deaths, often in their most productive years.

The microorganisms against which we struggle include dreaded bacteria, such as those that cause anthrax, bubonic plague, and tuberculosis, as well as those that cause much more common infections like Streptococcus pneumoniae (ear infections, pneumonia, and meningitis), Staphylococcus aureus (boils and abscesses), and Streptococcus pyogenes (strep throat and rheumatic fever). Other microorganisms including fungi (Aspergillus fumigatis), malarial parasites (Plasmodium falciparum), and the human immunodeficiency virus (HIV) may also become resistant to anti-infective agents.

Beginning around the middle of the 20th century, major advances in the development of antimicrobial agents, better understanding of how infections spread in hospitals and community settings, and better access to clean water that was safe for drinking helped reduce the global impact of infectious diseases on human health. Penicillin, which became available for use in the early 1940s, is an excellent example of a new antimicrobial agent that reduced the morbidity and mortality of diseases such as pneumococcal pneumonia and staphylococcal sepsis by half.

However, the euphoria over the potential conquest of infectious diseases was short-lived, as bacteria became resistant to the new wonder drugs. As use of antimicrobial agents became widespread, resistance spread and the array of different mechanisms of resistance increased. Once again, humans had to struggle to gain the upper hand against infections even as the number of new antibacterial agents began to dwindle. Herein, the rise of resistance to antibacterial agents will be reviewed.

How Do Antibacterial Agents Work? Most antimicrobial agents used for the treatment of bacterial infections can be categorized according to their principal mechanism of action. There are four major modes of action: (1) interference with cell wall synthesis, (2) inhibition of protein synthesis, (3) interference with nucleic acid synthesis, and (4) inhibition of a metabolic pathway (Tenover, 2006).

Antibacterial drugs that work by inhibiting bacterial cell wall synthesis include the p-lactams, such as the penicillins, cephalosporins, carbapenems, and monobactams, and the glycopeptides, including vancomycin and teicoplanin. p-lactam agents inhibit synthesis of the bacterial cell wall by interfering with the enzymes required for the synthesis of the peptidoglycan layer. Vancomycin and teicoplanin also interfere with cell wall synthesis by preventing the cross-linking steps required for stable cell wall synthesis.

Six different classes of drugs, the macrolides, aminoglycosides, tetracyclines, chloramphenicol, streptogramins, and oxazolidinones, all inhibit bacterial protein synthesis. Bacterial ribosomes, which are the site of bacterial protein synthesis, differ in structure from their counterparts in eukaryotic cells. Antibacterial agents take advantage of these differences to selectively inhibit bacterial growth. Macrolides, aminoglycosides, and tetracyclines bind to the 50S subunit of the ribosome, while choramphenicol binds to the 50S subunit.

The class of antimicrobial agents known as fluoroquinolones (which includes widely used drugs such as ciprofloxacin and levofloxacin) disrupt DNA synthesis in the bacterial cell, causing double-strand DNA breaks during DNA replication. Sulfonamides and trimethoprim, on the other hand, block the folic acid synthesis pathway, which ultimately inhibits DNA synthesis. The common antibacterial drug combination trimethoprim (a folic acid analog) plus sulfamethoxazole (a sulfonamide) inhibits two steps in the enzymatic pathway for bacterial folate synthesis and thus work in synergy with one another.

Another way of inhibiting bacterial cells is by disrupting their inner membranes. Drugs such as polymyxin B and colistin increase the permeability of the membrane, which makes the cells leaky. Daptomycin, a cyclic lipopeptide, apparently inserts its lipid tail into the bacterial cell membrane causing membrane depolarization, which also kills bacterial cells.