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Allied Health Microbiology: 10.4 Drug Resistance

Allied Health Microbiology
10.4 Drug Resistance
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table of contents
  1. Cover
  2. Title Page
  3. Copyright
  4. Table Of Contents
  5. Preface
  6. Forward
  7. Chapter 1: An Invisible World
    1. 1.1 What Our Ancestors Knew
    2. 1.2 A Systematic Approach
    3. 1.3 Types of Microorganisms
    4. Summary
  8. Chapter 2: The Cell
    1. 2.1 Spontaneous Generation
    2. 2.2 Foundations of Modern Cell Theory
    3. 2.3 Unique Characteristics of Prokaryotic Cells
    4. Summary
  9. Chapter 3: Prokaryotic Diversity
    1. 3.1 Prokaryote Habitats, Relationships, and Microbiomes
    2. Summary
  10. Chapter 4: The Eukaryotes of Microbiology
    1. 4.1 Unicellular Eukaryotic Parasites
    2. 4.2 Parasitic Helminths
    3. 4.3 Fungi
    4. Summary
  11. Chapter 5: Acellular Pathogens
    1. 5.1 Viruses
    2. 5.2 The Viral Life Cycle
    3. 5.3 Prions
    4. Summary
  12. Chapter 6: Microbial Biochemistry
    1. 6.1 Microbial Biochemistry
    2. Summary
  13. Chapter 7: Microbial Growth
    1. 7.1 How Microbes Grow
    2. 7.2 Oxygen Requirements for Microbial Growth
    3. 7.3 The Effects of pH on Microbial Growth
    4. 7.4 Temperature and Microbial Growth
    5. Summary
  14. Chapter 8: Modern Applications of Microbial Genetics
    1. 8.1 Whole Genome Methods and Pharmaceutical Applications of Genetic Engineering
    2. 8.2 Gene Therapy
    3. Summary
  15. Chapter 9: Control of Microbial Growth
    1. 9.1 Controlling Microbial Growth
    2. 9.2 Testing the Effectiveness of Antiseptics and Disinfectants
    3. Summary
  16. Chapter 10: Antimicrobial Drugs
    1. 10.1 Fundamentals of Antimicrobial Chemotherapy
    2. 10.2 Mechanisms of Antibacterial Drugs
    3. 10.3 Mechanisms of Other Antimicrobial Drugs
    4. 10.4 Drug Resistance
    5. 10.5 Testing the Effectiveness of Antimicrobials
    6. 10.6 Current Strategies for Antimicrobial Discovery
    7. Summary
  17. Chapter 11: Microbial Mechanisms of Pathogenicity
    1. 11.1 Characteristics of Infectious Disease
    2. 11.2 How Pathogens Cause Disease
    3. 11.3 Virulence Factors of Bacterial and Viral Pathogens
    4. Summary
  18. Chapter 12: Disease and Epidemiology
    1. 12.1 The Language of Epidemiologists
    2. 12.2 Tracking Infectious Diseases
    3. 12.3 Modes of Disease Transmission
    4. 12.4 Global Public Health
    5. Summary
  19. Chapter 13: Innate Nonspecific Host Defenses
    1. 13.1 Physical Defenses
    2. 13.2 Chemical Defenses
    3. 13.3 Cellular Defenses
    4. 13.4 Pathogen Recognition and Phagocytosis
    5. 13.5 Inflammation and Fever
    6. Summary
  20. Chapter 14: Adaptive Specific Host Defenses
    1. 14.1 Overview of Specific Adaptive Immunity
    2. 14.2 Major Histocompatibility Complexes and Antigen-Presenting Cells
    3. 14.3 T Lymphocytes and Cellular Immunity
    4. 14.4 B Lymphocytes and Humoral Immunity
    5. 14.5 Vaccines
    6. Summary
  21. Chapter 15: Diseases of the Immune System
    1. 15.1 Hypersensitivities
    2. 15.2 Autoimmune Disorders
    3. 15.3 Organ Transplantation and Rejection
    4. Summary
  22. Chapter 16: Skin and Eye Infections
    1. 16.1 Anatomy and Normal Microbiota of the Skin and Eyes
    2. 16.2 Bacterial Infections of the Skin and Eyes
    3. 16.3 Viral Infections of the Skin and Eyes
    4. 16.4 Mycoses of the Skin
    5. 16.5 Helminthic Infections of the Skin and Eyes
    6. Summary
  23. Chapter 17: Respiratory System Infections
    1. 17.1 Anatomy and Normal Microbiota of the Respiratory Tract
    2. 17.2 Bacterial Infections of the Respiratory Tract
    3. 17.3 Viral Infections of the Respiratory Tract
    4. Summary
  24. Chapter 18: Urogenital System Infections
    1. 18.1 Anatomy and Normal Microbiota of the Urogenital Tract
    2. 18.2 Bacterial Infections of the Urinary System
    3. 18.3 Bacterial Infections of the Reproductive System
    4. 18.4 Viral Infections of the Reproductive System
    5. 18.5 Fungal Infections of the Reproductive System
    6. 18.6 Protozoan Infections of the Urogenital System
    7. Summary
  25. Chapter 19: Digestive System Infections
    1. 19.1 Anatomy and Normal Microbiota of the Digestive System
    2. 19.2 Microbial Diseases of the Mouth and Oral Cavity
    3. 19.3 Bacterial Infections of the Gastrointestinal Tract
    4. 19.4 Viral Infections of the Gastrointestinal Tract
    5. 19.5 Protozoan Infections of the Gastrointestinal Tract
    6. 19.6 Helminthic Infections of the Gastrointestinal Tract
    7. Summary
  26. Chapter 20: Circulatory and Lymphatic System Infections
    1. 20.1 Anatomy of the Circulatory and Lymphatic Systems
    2. 20.2 Bacterial Infections of the Circulatory and Lymphatic Systems
    3. 20.3 Viral Infections of the Circulatory and Lymphatic Systems
    4. 20.4 Parasitic Infections of the Circulatory and Lymphatic Systems
    5. Summary
  27. Chapter 21: Nervous System Infections
    1. 21.1 Anatomy of the Nervous System
    2. 21.2 Bacterial Diseases of the Nervous System
    3. 21.3 Acellular Diseases of the Nervous System
    4. Summary
  28. Creative Commons License
  29. Recommended Citations
  30. Versioning

10.4 Drug Resistance

Learning Objectives

  • Explain the concept of drug resistance
  • Describe how microorganisms develop or acquire drug resistance
  • Describe the different mechanisms of antimicrobial drug resistance

Antimicrobial resistance is not a new phenomenon. In nature, microbes are constantly evolving in order to overcome the antimicrobial compounds produced by other microorganisms. Human development of antimicrobial drugs and their widespread clinical use has simply provided another selective pressure that promotes further evolution. Several important factors can accelerate the evolution of drug resistance. These include the overuse and misuse of antimicrobials, inappropriate use of antimicrobials, subtherapeutic dosing, and patient noncompliance with the recommended course of treatment.

Exposure of a pathogen to an antimicrobial compound can select for chromosomal mutations conferring resistance, which can be transferred vertically to subsequent microbial generations and eventually become predominant in a microbial population that is repeatedly exposed to the antimicrobial. Alternatively, many genes responsible for drug resistance are found on plasmids or in transposons that can be transferred easily between microbes through horizontal gene tranfer. Small pieces of DNA called transposons also have the ability to move resistance genes between plasmids and chromosomes to further promote the spread of resistance.

Mechanisms for Drug Resistance

There are several common mechanisms for drug resistance, which are summarized in Figure 10.9. These mechanisms include enzymatic modification of the drug, modification of the antimicrobial target, and prevention of drug penetration or accumulation.

There are multiple strategies that microbes use to develop resistance to antimicrobial drugs. (Not shown: target overproduction, target mimicry, and enzymatic bypass). (credit: modification of work by Gerard D Wright)
Figure 10.9 There are multiple strategies that microbes use to develop resistance to antimicrobial drugs. (Not shown: target overproduction, target mimicry, and enzymatic bypass). (credit: modification of work by Gerard D Wright)

Drug Inactivation

Resistance genes may code for enzymes that chemically modify an antimicrobial, thereby inactivating it, or destroy an antimicrobial through hydrolysis. Resistance to many types of antimicrobials occurs through this mechanism.

Prevention of Cellular Uptake or Efflux

Microbes may develop resistance mechanisms that involve inhibiting the accumulation of an antimicrobial drug, which then prevents the drug from reaching its cellular target. This strategy is common among gram-negative pathogens and can involve changes in outer membrane lipid composition, porin channel selectivity, and/or porin channel concentrations. Additionally, many gram-positive and gram-negative pathogenic bacteria produce efflux pumps that actively transport an antimicrobial drug out of the cell and prevent the accumulation of drug to a level that would be antibacterial.

Target Modification

Because antimicrobial drugs have very specific targets, structural changes to those targets can prevent drug binding, rendering the drug ineffective. Through spontaneous mutations in the genes encoding antibacterial drug targets, bacteria have an evolutionary advantage that allows them to develop resistance to drugs. This mechanism of resistance development is quite common. Examples of this resistance strategy include alterations in

  • penicillin-binding proteins (PBPs), providing resistance to penicillins
  • ribosome subunits, providing resistance to macrolides, tetracyclines, and aminoglycosides;
  • lipopolysaccharide (LPS) structure, providing resistance to polymyxins;
  • RNA polymerase, providing resistance to rifampin;
  • DNA gyrase, providing resistance to fluoroquinolones;
  • metabolic enzymes, providing resistance to sulfa drugs, sulfones, and trimethoprim
  • peptidoglycan subunit peptide chains, providing resistance to glycopeptides.

Target Overproduction or Enzymatic Bypass

When an antimicrobial drug functions as an antimetabolite, targeting a specific enzyme to inhibit its activity, there are additional ways that microbial resistance may occur. First, the microbe may overproduce the target enzyme such that there is a sufficient amount of antimicrobial-free enzyme to carry out the proper enzymatic reaction. Second, the bacterial cell may develop a bypass that circumvents the need for the functional target enzyme. Both of these strategies have been found as mechanisms of sulfonamide resistance.

  • List several mechanisms for drug resistance.

Multidrug-Resistant Microbes and Cross Resistance

From a clinical perspective, our greatest concerns are multidrug-resistant microbes (MDRs) and cross resistance. MDRs are colloquially known as “superbugs” and carry one or more resistance mechanism(s), making them resistant to multiple antimicrobials. In cross-resistance, a single resistance mechanism confers resistance to multiple antimicrobial drugs. For example, having an efflux pump that can export multiple antimicrobial drugs is a common way for microbes to be resistant to multiple drugs by using a single resistance mechanism.

Methicillin-Resistant Staphylococcus aureus (MRSA)

Methicillin, a semisynthetic penicillin, was designed to resist inactivation by β-lactamases. Unfortunately, soon after the introduction of methicillin to clinical practice, methicillin-resistant strains of S. aureus appeared and started to spread. The mechanism of resistance, acquisition of a new low-affinity PBP, provided S. aureus with resistance to all available β-lactams. Strains of methicillin-resistant S. aureus (MRSA) are widespread opportunistic pathogens and a particular concern for skin and other wound infections, but may also cause pneumonia and septicemia. Although originally a problem in health-care settings (hospital-acquired MRSA [HA-MRSA]), MRSA infections are now also acquired through contact with contaminated members of the general public, called community-associated MRSA (CA-MRSA). Approximately one-third of the population carries S. aureus as a member of their normal nasal microbiota without illness, and about 6% of these strains are methicillin resistant.[1][2]

Multidrug-Resistant Mycobacterium tuberculosis

The emergence of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) is also of significant global concern. MDR-TB strains are resistant to both rifampin and isoniazid, the drug combination typically prescribed for treatment of tuberculosis. XDR-TB strains are additionally resistant to any fluoroquinolone and at least one of three other drugs (amikacin, kanamycin, or capreomycin) used as a second line of treatment, leaving these patients very few treatment options. Both types of pathogens are particularly problematic in immunocompromised persons, including those suffering from HIV infection. The development of resistance in these strains often results from the incorrect use of antimicrobials for tuberculosis treatment, selecting for resistance.

  • How does drug resistance lead to superbugs?

Link to Learning

To learn more about the top 18 drug-resistant threats to the US, visit the CDC’s website (https://openstax.org/l/22CDC18drugres).


  1. A.S. Kalokhe et al. “Multidrug-Resistant Tuberculosis Drug Susceptibility and Molecular Diagnostic Testing: A Review of the Literature. American Journal of the Medical Sciences 345 no. 2 (2013):143–148. ↵
  2. Centers for Disease Control and Prevention. “Methicillin-Resistant Staphylococcus aureus (MRSA): General Information About MRSA in the Community.” http://www.cdc.gov/mrsa/community/index.html. Accessed June 2, 2016 ↵

Annotate

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10.5 Testing the Effectiveness of Antimicrobials
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