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Salem Health: Infectious Diseases & Conditions, 2nd Edition

Multi-Drug Resistance

Category: Treatment

Definition

Multi-drug resistance refers to the ability of bacteria to become resistant to many different antibiotics. An antibiotic is a small molecule that is able to kill or otherwise inhibit the replication of bacteria because of its interaction with a specific target. Resistance means that the antibiotic no longer is able to interact with the specific target; multi-drug resistance means that many different types of antibiotics are unable to interact with many different specific targets.

Specific Targets for the Interaction of Antibiotics with Bacteria

In order to understand multi-drug resistance, it is useful to first understand how antibiotics are able to interact with specific targets of bacteria that will then lead to either the killing or inhibition of replication of bacteria. There are multiple ways that antibiotics can kill bacteria or inhibit their growth; the three most common mechanisms of action for antibiotics are as follows:

Inhibition of the Construction of the Bacterial Cell Wall

Antibiotics can inhibit the construction of the cell wall of the bacteria. This generally does not rapidly kill the bacteria, but over time may lead to the death of the bacteria.

Two antibiotic resistance tests in petri dishes. The E. coli growing in the left plate is susceptible to the antibiotics contained in the paper circles, while the right plate shows resistance to several antibiotics. Photo by Dr. Graham Beards via Wikimedia Commons.

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Inhibition of the Ability of the Bacteria to Make Proteins

Antibiotics can inhibit the ability of the bacteria to make proteins. This generally does not rapidly kill the bacteria, but over time also may lead to the death of the bacteria.

Inhibition of the Ability of the Bacteria to Make DNA

Antibiotics can inhibit the ability of the bacteria to make DNA. The genetic material of bacteria is usually contained in a circular molecule of DNA; inhibition of the ability of the bacteria to make DNA generally leads to rapid death of the bacteria.

Important Bacterial Resistance Mechanisms

Bacteria have developed way to counter the ability of antibiotics to kill or inhibit their growth. These bacterial resistance mechanisms are important as they make the antibiotics less effective. When bacteria have many different resistant mechanisms to antibiotics, they are described as having “multi-drug resistance”. Important mechanisms of resistance are as follows:

Decreased Penetration of the Antibiotic through the Bacterial Cell Wall

Decreased penetration of the antibiotic through the bacterial cell wall is an important bacterial resistance mechanism and is best exemplified by enteric bacillary bacteria such as Escherichia coli. These enteric bacillary bacteria have an outer membrane that serves as a penetration barrier; some permeability in this outer membrane is achieved by water-filled diffusion channels called “porins” that allow passage of needed nutrients. Reduced expression of these porin channels by mutation of the bacterial DNA is an example of a bacterial resistance mechanism involving decreased penetration.

Increased Excretion (Efflux) of the Antibiotic out of the Bacterial Cell

Bacteria are able to excrete antibiotics out of the bacterial cell; the mechanism that does this is known as an “efflux pump”. Bacterial efflux pumps have been recognized as an important mechanism of resistance. Efflux pumps are able to pump many different types of antibiotics out of the bacterial cell; this wide specificity in the different types of antibiotics can itself result in multi-drug resistance.

Destruction or Inactivation of the Antibiotic

Bacteria often are able to either destroy or inactivate antibiotics; destruction/inactivation of the antibiotic is yet another important mechanism of resistance. Destruction of the antibiotic is exemplified by beta-lactamase, which is an enzyme that can destroy penicillin and cephalosporin antibiotics (i.e., beta-lactam antibiotics). Some bacteria have this enzyme while others do not. Inactivation of an antibiotic is exemplified by aminoglycoside-inactivation enzymes, which are able to inactivate aminoglycosides such as gentamicin by adding large bulky molecules that alter the ability of the aminoglycoside to interact with the bacterial target site.

Alteration of the Bacterial Target Site of the Antibiotic

Bacteria often are able to alter the bacterial target site of the antibiotic. Alteration of the bacterial target site of the antibiotic is a common and important mechanism of resistance. For example, penicillin-binding proteins are catalysts that are involved in the construction of the bacterial cell wall; these penicillin-binding proteins can be altered such that they no longer are able to function as catalysts in the construction of the bacterial cell wall. Similarly, ribosomes are involved in the manufacturing of proteins by the bacteria and are the targets of macrolide antibiotics such as erythromycin. These ribosomes can be altered such that the target site for the macrolide antibiotic can no longer interact with this site.

Development of Bypass Pathways around Bacterial Target Sites

Although less common than the aforementioned resistance mechanisms, development of bypass pathways around the bacterial target sites can occur. An example of the development of a bypass pathway is seen with the antibiotic vancomycin and enterococcal bacteria. The target site for vancomycin is the D-alanine-D-alanine terminal of the pentapeptide used in the cross-linking of the peptidoglycan strands that make up the cell wall. Some strains of enterococci can alter this D-alanine-D-alanine terminal to D-alanine-D-lactate or D-alanine-D-serine, which reduces the ability of vancomycin to bind to this terminal. This results in resistance of these enterococci to vancomycin.

The Role of Transmissible Genetic Elements in Multi-Drug Resistance

Some bacteria naturally possess the genetic information for one or more of the resistance mechanisms described. These bacteria are said to be “intrinsically resistant” to those antibiotics vulnerable to the specific mechanisms of the bacteria. Many of these resistance mechanisms are in genetic elements, like plasmids and transposons, that can be transferred to other bacteria. An otherwise vulnerable bacterium can acquire many of these resistance mechanisms and thus become resistant. In fact, some of these transmissible genetic elements can have genetic information for more than one resistance mechanism. As a result, bacteria receiving these plasmids or transposons can acquire multiple resistance mechanisms to many different types of antibiotics. The bacteria become “multi-drug resistant” and have sometimes been dubbed “superbugs”. Transmission of plasmids and transposons containing multiple resistance mechanisms has allowed wide-spread proliferation and dissemination of multi-drug resistant bacteria.

Impact

Multi-drug resistance and superbugs are now commonly encountered in medical centers around the world. Multi-drug resistance makes treating patients with infections caused by these resistant bacteria very difficult. Considering there are not many new antibiotics being developed, multi-drug resistance is of great concern to physicians treating infections. Understanding this concept is important for both patients and healthcare providers.

Further Reading

1 

Levy, SB. “Multidrug resistance – a sign of the times.” New England Journal of Medicine, 1998; 338: 1376-1378.

2 

Wise RA. “A review of the mechanisms of action for antimicrobial agents.” Canadian Respiratory Journal 1999; 6(Supplement A): A20-A22.

3 

Stratton CW. “Molecular mechanisms of action for antimicrobial agents: General principles and mechanisms for selected classes of antibiotics.” In: Antibiotics in Laboratory Medicine, Sixth Edition, Chapter 10, pp 450-495.Amsterdam, D. (Ed.), Lippencott Williams & Wilkins Company, Baltimore, MD, 2015.

4 

Chang H-H, Cohen T, Grad YH, Hanage WP, O’Brien TF, Lipsitch M. “Origin and proliferation of multiple-drug resistance in bacterial pathogens.” Microbiology & Molecular Biology Review, 2015. 79:101-1016.

5 

Lobanovska M, Pilla G. “Penicillin’s discovery and antibiotic resistance: Lessons for the future?” Yale Journal of Biology & Medicine 2017; 90:135-145.

Web Sites of Interest

CDC

https://www.cdc.gov/drugresistance/index.html

World Health Organization

http://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

ReAct Group: Action on Antibiotic Resistance

https://www.reactgroup.org/toolbox/understand/antibiotic-resistance/multidrug-resistant-bacteria/

Drugs.com

https://www.drugs.com/article/antibiotic-resistance.html

See also: Alternative therapies; Antibiotics: Experimental; Antibiotics: Types; Antifungal drugs: Types; Antiparasitic drugs: Types; Bacterial infections; Cephalosporin antibiotics; Home remedies; Hospitals and infectious disease; Iatrogenic infections; Infection; Microbiology; Mutation of pathogens; Over-the-counter (OTC) drugs; Parasitic diseases; Pathogenicity; Pathogens; Public health; Secondary infection; Superbacteria; Treatment of bacterial infections.

Citation Types

Type
Format
MLA 9th
"Multi-Drug Resistance." Salem Health: Infectious Diseases & Conditions, 2nd Edition, edited by H. Bradford Hawley, Salem Press, 2020. Salem Online, online.salempress.com/articleDetails.do?articleName=Infect2e_0373.
APA 7th
Multi-Drug Resistance. Salem Health: Infectious Diseases & Conditions, 2nd Edition, In H. B. Hawley (Ed.), Salem Press, 2020. Salem Online, online.salempress.com/articleDetails.do?articleName=Infect2e_0373.
CMOS 17th
"Multi-Drug Resistance." Salem Health: Infectious Diseases & Conditions, 2nd Edition, Edited by H. Bradford Hawley. Salem Press, 2020. Salem Online, online.salempress.com/articleDetails.do?articleName=Infect2e_0373.