Drug resistance is a critical issue in microbiology. Microorganisms adapt to survive antimicrobial drugs, making infections harder to treat. This phenomenon affects bacteria, viruses, and fungi, limiting treatment options and increasing healthcare costs.

Resistance develops through intrinsic characteristics, genetic changes, or gene acquisition. Selective pressure from antimicrobial use accelerates this process. Understanding these mechanisms is crucial for developing strategies to combat the growing threat of drug-resistant infections.

Mechanisms and Impact of Drug Resistance

Drug resistance and antimicrobial effectiveness

• Drug resistance develops when microorganisms adapt to survive and multiply despite the presence of an antimicrobial drug that would typically inhibit or kill them (bacteria, viruses, fungi)
  • Diminishes the effectiveness of antimicrobial treatments making infections harder to control
  • Necessitates higher doses or alternative drugs to combat resistant infections
• Resistant microorganisms can disseminate leading to increased prevalence of drug-resistant infections (methicillin-resistant Staphylococcus aureus (MRSA))
  • Presents a major threat to public health by limiting treatment options
  • Results in increased healthcare expenditures and extended hospital stays
• Antimicrobial resistance can emerge against various drug classes encompassing antibiotics, antivirals, and antifungals (penicillins, fluoroquinolones, azoles)
  • The minimum inhibitory concentration (MIC) of drugs often increases as resistance develops

Development of antimicrobial resistance

• Intrinsic resistance: Certain microorganisms have inherent characteristics that render them naturally resistant to specific antimicrobials
  • Gram-negative bacteria's outer membrane functions as a barrier conferring intrinsic resistance to certain antibiotics (polymyxins)
• Acquired resistance: Microorganisms gain resistance through genetic alterations or acquisition of resistance genes
  • Mutations in genes targeted by antimicrobials can modify drug binding sites or decrease drug uptake (rifampin resistance in Mycobacterium tuberculosis)
  • Horizontal gene transfer enables resistance genes to propagate among microorganisms via mechanisms including:
    • Conjugation: Exchange of genetic material through direct cell-to-cell contact (plasmid-mediated resistance)
    • Transformation: Incorporation of naked DNA from the surrounding environment (antibiotic resistance in Streptococcus pneumoniae)
    • Transduction: Transfer of genetic material mediated by bacteriophages (phage-mediated resistance in Escherichia coli)
• Selective pressure: Exposure to antimicrobials favors the survival and growth of resistant strains
  • Inappropriate or excessive use of antimicrobials accelerates the development and spread of resistance (antibiotic overuse in agriculture)

Multidrug Resistance and Superbugs

• Multidrug resistance occurs when microorganisms develop resistance to multiple classes of antimicrobial drugs
  • Often results from the accumulation of multiple resistance mechanisms or the acquisition of antibiotic-resistant genes
• Superbugs are strains of bacteria that have become resistant to multiple types of antibiotics
  • Pose significant challenges in healthcare settings and can lead to severe, difficult-to-treat infections
• The One Health approach recognizes the interconnectedness of human, animal, and environmental health in addressing antimicrobial resistance
• Antibiotic stewardship programs aim to optimize antimicrobial use and prevent the development of resistance

Resistance Mechanisms Across Microorganisms

Mechanisms of resistance across microorganisms

• Bacteria:
  • Enzymatic modification or breakdown of antimicrobials
    • Beta-lactamases catalyze the hydrolysis of beta-lactam antibiotics rendering them ineffective (extended-spectrum beta-lactamases (ESBLs))
  • Alteration of drug targets
    • Mutations in genes encoding drug target proteins can diminish drug binding affinity (fluoroquinolone resistance in Pseudomonas aeruginosa)
  • Reduced drug uptake or increased efflux
    • Modifications in cell wall or membrane permeability restrict drug entry (vancomycin resistance in Enterococcus)
    • Efflux pumps actively expel antimicrobials from the cell (tetracycline resistance in E. coli)
• Viruses:
  • Mutations in viral enzymes targeted by antiviral drugs
    • Mutations in HIV reverse transcriptase can impart resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (lamivudine resistance)
  • Alterations in viral proteins that interact with antiviral drugs
    • Changes in viral envelope proteins can decrease the efficacy of entry inhibitors (maraviroc resistance in HIV)
  • Viral genome diversity and high mutation rates
    • Rapid replication and error-prone viral polymerases contribute to the emergence of resistant variants (influenza virus resistance to adamantanes)
• Fungi:
  • Overexpression of drug target enzymes
    • Increased production of enzymes like lanosterol 14α-demethylase can offset the inhibitory effects of azole antifungals (fluconazole resistance in Candida albicans)
  • Mutations in drug target genes
    • Alterations in ergosterol biosynthesis pathway enzymes can reduce the binding affinity of antifungal agents (echinocandin resistance in Candida glabrata)
  • Efflux pump overexpression
    • Enhanced activity of efflux pumps, such as Cdr1p and Mdr1p, can actively remove antifungal drugs from fungal cells (azole resistance in Candida species)