Multidrug Resistance in Bacteria

Sometimes the miracles of modern medicine can have their downsides. A streak of 20th century medical innovation created many important antibiotics used today, and was responsible for dramatically lowering the impact of infectious disease around the globe. However, the widespread distribution and usage of these same antibiotics served as a sort of evolutionary screening mechanism, selecting for tougher and tougher strains of bacteria with increasing antibiotic resistance. Antibiotic resistance is recognized by the CDC as “one of the biggest public health challenges of our time,” and the concentration of resistant bacterial strains in hospital environments is an especially grave threat to patients whose defenses may already be weakened by injury or disease. Creating novel solutions to the problem of antibiotic resistance requires a deep understanding of resistance mechanisms. Today’s blog post will discuss a few key examples.

The wide-spread use of penicillin throughout the 20th century has lead to “fitter” bacteria that are resistant to the varieties of medicine available to fight them. Glass phial of British Standard penicillin, London, England,. Credit: Science Museum, London.CC BY

Bacterial antibiotic resistance mechanisms typically use one of a few strategies: bacterial systems can modify an antibiotic molecule so it can’t bind its target, destroy the antibiotic molecule, mutate the antibiotic’s target protein so that the bacterium is no longer affected, borrow a replacement protein from other bacterial species, or simply try to remove the drug from the cell altogether.

Antibiotic Neutralization

Neutralization of antibiotics by a resistance enzyme is one of the most common mechanisms for drug resistance. This approach is particularly useful against antibiotic frameworks developed from naturally occurring molecules (as opposed to synthetically derived frameworks). One antibiotic class that is commonly neutralized is the aminoglycosides, such as kanamycin, tobramycin, and amikacin. Resistance enzymes can add or remove segments of antibiotic molecules, rendering them useless. The antibiotics that these enzymes target were derived from molecules originally used as antibacterial weapons by other bacteria and microorganisms. In response, bacteria created these neutralizing enzymes as self-defense mechanisms. Because bacterial strains lack a long evolutionary familiarity with synthetic molecule frameworks, these resistance enzymes are far less effective against them. Unfortunately, no new synthetic antibiotic frameworks have been created or discovered since the 1980’s, and there are plenty of other resistance mechanisms bacteria use to evade them.

Antibiotic Destruction

Closely related to the antibiotic neutralizing enzymes, antibiotic destruction enzymes are responsible for countering the effect of ꞵ-lactams, the class of drugs that includes penicillins, cephalosporins, carbapenems, and monobactams. The enzymes that destroy these drugs are known as ꞵ-lactamases, and they utilize a process called hydrolysis to break apart and destroy the drugs.

Salmonella Typhimurium infection of a human epithelial cell. Credit: David Goulding, Wellcome Trust Sanger Institute. CC BY-NC

Alteration of Target Protein

Antibiotics are typically small molecule drugs that inhibit the function of a critical protein in the bacterial system, referred to as the target protein. This target protein is critical enough to the bacterial cell that its loss will result in the death of the bacterium. In order to inhibit the target protein, many antibiotics mimic the appearance of a molecule, or substrate, that the target protein would normally bind to. They then bind more tightly to the active site of the target protein than the substrate, preventing the target protein from carrying out its function. This process is known as competitive inhibition. One way bacteria can resist this type of drug is to mutate the target protein in such a way that it reduces the binding affinity of the drug without reducing the enzymatic activity of the target.

Replacement of Target Protein

Another mechanism by which bacteria gain resistance to antibiotics is by using horizontal gene transfer to replace or modify the target protein. Horizontal gene transfer refers to the capacity of some bacteria to scavenge or exchange genes with other bacteria. This is mainly done either through the direct transfer of small DNA segments called plasmids, or through bacteriophage transduction, in which viruses pick up segments of DNA from one host and inject them into another. The transfer of genes allows bacteria to swap their copy of a target protein with a version from another source that is not affected by the drug.

Preventing Drug Access to Targets

Instead of modifying the drug’s targets themselves, bacteria can attempt to remove antibiotics from their system altogether. The tetracycline repressor (TetR) protein is an excellent example of this. TetR binds to tetracycline before the drug has an opportunity to bind and inhibit its target, the bacterial ribosome. It then brings the antibiotic to an anti-porter, which pumps tetracycline back to the exterior of the cell. There are a variety of drug specific efflux pumps that all serve to remove antibiotics from the cytoplasm of the bacterial cell. These specific pumps are used in conjunction with multidrug efflux pumps as part of a broader bacterial toxin response system which moves dangerous molecules out of the cell.

The Role for Antibodies

It’s clear that antibiotic resistance is not a simple problem, but a complex system that is adaptive and capable of circumventing many of the tools available to us today. The threat of multidrug resistant bacterial infections is very real. It’s not just a danger in areas with an overuse of antibiotics, because human travel allows these “superbugs” to traverse continents with us as their hosts. One hope for the future is designer antibodies — used in conjunction with existing antibiotics, or as a new wave of therapeutics to replace current methods. Either way, the medical industry is hard at work developing adaptive approaches for this growing problem.

Links and Citations:

1. Adedeji W. A. (2016). THE TREASURE CALLED ANTIBIOTICS. Annals of Ibadan postgraduate medicine, 14(2), 56–57.
2. Munita, J. M., & Arias, C. A. (2016). Mechanisms of Antibiotic Resistance. Microbiology spectrum, 4(2), 10.1128/microbiolspec.VMBF-0016–2015. doi:10.1128/microbiolspec.VMBF-0016–2015
3. Nikaido H. (2009). Multidrug resistance in bacteria. Annual review of biochemistry, 78, 119–146. doi:10.1146/annurev.biochem.78.082907.145923

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