Drug Resistance

1. Introduction

Whenever microbes are exposed to something that affects their survival, those that are best able to resist are able to survive to reproduce most effectively. In this way, microbes have always evolved to improve their ability to survive in changing conditions. Exposure to antimicrobial medications is another factor that affects some individual microbes more strongly than others, selecting for those with traits that help them survive.

It is important to be aware of factors that contribute to drug resistance (the ability to survive exposure to a drug), and to use medications wisely in ways that reduce the risk of resistance. Understanding drug resistance also helps researchers develop treatment approaches that reduce this risk.

Factors that increase the risk of drug resistance include the following:

1. Overuse and misuse of antimicrobials
2. Inappropriate use of antimicrobials
3. Subtherapeutic dosing (i.e., giving a patient too little of an antibiotic to effectively treat the pathogen)
4. Patients choosing to use medications in ways other than recommended (e.g., using other people’s medications, stopping medications too early, not taking medications regularly)

term to know

Drug Resistance

The ability to survive exposure to a drug.

2. Mechanisms of Drug Resistance

There are many ways in which microbes can become resistant to antimicrobials. These mechanisms include enzymatic modification of the drug so that it no longer harms the microbe, modifying the target of the drug so that it is no longer affected and preventing the drug from entering the cell or accumulating in the cell.

The image below summarizes the following important mechanisms of resistance and medications affected: efflux pumps that move medications out of the cell, blocked penetration that keeps the medication from entering the cell, inactivation of enzymes, and target modification so that drug targets are no longer affected.

Prevention of cellular uptake (blocked penetration) or efflux involves either keeping a medication out of the cell or removing it from the cell so that it does not accumulate. This prevents the drug from reaching its target within the cell. This strategy is especially common among gram-negative pathogens and can involve changes in outer membrane composition, selectivity of protein channels, and/or concentrations of protein channels. Efflux pumps that actively transport the drug out of the cell are common mechanisms of resistance to β-lactams, tetracyclines, and fluoroquinolones. It is common for a single efflux pump to be able to transport more than one type of antimicrobial.

Drug modification or inactivation can result from the production of enzymes that chemically modify an antimicrobial or destroy it through hydrolysis. Aminoglycoside resistance can occur through enzymatic transfer of chemical groups to the antimicrobial molecule, impairing the binding of the drug to its target. One common mechanism is enzymatic hydrolysis of the β-lactam bond within the β-lactam ring of antimicrobials that have them. This is often accomplished by β-lactamases. Inactivation of rifampin commonly occurs through glycosylation, phosphorylation, or adenosine diphosphate (ADP) ribosylation. Finally, resistance to macrolides and lincosamides can also occur because of enzymatic inactivation or modification.

Target modification involves changing the target of the antimicrobial medication. Some examples include modification of the active site of penicillin-binding proteins (PBP) that inhibit the binding of β-lactam drugs, acquisition of low-affinity PBP that leads to methicillin resistance in some strains of Staphylococcus aureus, and many other mechanisms. Other examples include modifications to ribosomes, lipopolysaccharide structure, RNA polymerase, DNA gyrase, metabolic enzymes, and peptidoglycan subunit peptide chains.

Another possible mechanism of drug resistance is target overproduction or enzymatic bypass. Some antimicrobial drugs act as antimetabolites and inhibit enzymes. Microbes can respond by overproducing the target enzyme so that there is a sufficient amount available to perform the function even if some enzymes are inactivated. A bacterial cell may also develop a bypass mechanism so that the enzyme is not needed. For example, vancomycin resistance in S. aureus can involve decreased cross-linkage of peptide chains in the bacterial cell wall so that there are more targets for vancomycin binding on the outer cell wall that prevent vancomycin from penetrating deeper to block cell wall synthesis.

Finally, some microbes use target mimicry to produce proteins that resemble the target of the antimicrobial. The antimicrobial binds to the mimic, meaning that less is available to bind to the cellular targets that would harm the bacterium. Mycobacterium tuberculosis can produce a protein that resembles DNA called Mycobacterium fluoroquinolone resistance protein A (MfpA). DNA gyrase required for DNA replication binds to MfpA, which prevents fluoroquinolones from binding to DNA gyrase.

EXAMPLE

Have you ever developed a small skin infection, perhaps a bump that may seem to be a spider bite? These infections are sometimes caused by S. aureus. Because resistant strains of S. aureus are so common, health care providers have to take them into account in deciding on the best course of treatment. The Centers for Disease Control (CDC) regularly issues updates on the prevalence of resistant strains for particular types of infections and the treatment options available (see CDC, 2022).

3. Multidrug-Resistant Microbes and Cross-Resistance

An emerging concern is that increasing antibiotic resistance is leading to growing prevalence of multidrug-resistant microbes (MDRs) that are resistant to multiple antimicrobials. Additionally, it is increasingly common for microbes to exhibit cross-resistance, in which microbes have a single resistance mechanism that makes them resistant to multiple medications.

terms to know

Multidrug-Resistant Microbe (MDR)

A microbe that is resistant to multiple antimicrobials.

Cross-Resistance

A microbe has a single resistance mechanism that makes it resistant to multiple medications.

4. Examples of Medically Important Resistant Microbes

Unfortunately, MDRs and microbes that exhibit cross-resistance are becoming significant public health concerns. Several of the most clinically important examples are methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-resistant S. aureus (VRSA), vancomycin-intermediate S. aureus (VISA), extended-spectrum β-lactamase-producing gram-negative pathogens, carbapenem-resistant gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant M. tuberculosis (MDR-TB), and extensively drug-resistant M. tuberculosis (XDR-TB).

did you know

Resistant forms of tuberculosis are of particular concern. XDR-TB can only be treated with medications that are less effective than options available for other forms of tuberculosis. For immunocompromised individuals, the risk of both contracting and dying from these infections is elevated. The CDC recommends that health care professionals contact specialists for advice on managing XDR-TB infections as they can be challenging to treat (CDC, 2022).

watch

Drug-Resistant Bacteria

REFERENCES

CDC, Drug-Resistant TB. (2022, October, 13). Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Retrieved November 16, 2022, from www.cdc.gov/tb/topic/drtb/default.htm

CDC, Gonorrhea Treatment and Care. (2022, April 12). Division of STD Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Retrieved November 16, 2022, from www.cdc.gov/std/gonorrhea/treatment.htm