Antimicrobial Drugs and Their Evolution of Resistance

Antimicrobial Drugs

  • compounds that kill or control the growth of microorganisms in the host (in vivo)
  • effective antimicrobial drugs exhibit selective toxicity
  • they inhibit or kill the pathogens without adversely affecting the hosts
  • antimicrobial drugs classified based on their molecular structure, mechanism of action and spectrum of antimicrobial activity
  • major antimicrobial drug groups: antibacterial drugs (antibiotics and synthetic drugs), antifungal drugs, antiparasitic drugs, and antiviral drugs

How to Select Antimicrobial Drugs?

Based on:

  1. Nature of microbe causing the infection
  2. Degree of microbe’s sensitivity to various drugs
  3. The overall medical condition of the patient

Characteristics of the Ideal Antimicrobial Drugs

  • Selectively toxic to the microbe but non-toxic to the host cells
  • Microbicidal rather than microbistatic
  • Relatively soluble and functions even when highly diluted in the body fluids
  • Remains potent long enough to act and is not broken down or excreted prematurely
  • Not subject to the development of antimicrobial resistance
  • Complements or assists the activities of the host’s defenses
  • Remains active in the tissues and body fluids
  • Readily delivered to the site of infection
  • Not excessive in cost
  • Does not disrupt the host’s health by causing allergies or predisposing the host to other infections

Antimicrobial Drugs and Their Evolution of Resistance

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Classes of Antibacterial Antibiotics

1. Penicillins

  • Characterized by Alexander Fleming in 1929, isolated from fungus Penicillium chrysogenum
  • the large diverse group of compounds
  • Effective for controlling staphylococcal and pneumococcal infections than sulfa drugs
  • Consists of 3 parts: beta-lactam ring, thiazolidine ring, and variable/ acyl side chain
  • Penicillin G is active primarily against gram-positive bacteria because gram-negative bacteria are impermeable to the antibiotic, but the chemical modification of penicillin G structure changes the resulting antibiotic
  • Chemically modified semisynthetic penicillins (ampicillin, carbenicillin) are effective against gram-negative bacteria
  • β-lactamase-resistant semisynthetic penicillins: Oxacillin and methicillin

2. Cephalosporins

  • Produced by fungus Cephalosporium acremonium mold
  • Differ structurally from penicillins
  • Retain the β-lactam ring but have a six-member dihydrothiazine ring instead of the five-member thiazolidine ring
  • More resistant to the β-lactamases and cause fewer allergies reaction
  • Ceftriaxone for treatment of Neisseria gonorrhoeae infections

3. Aminoglycosides

  • antibiotics that contain amino sugars bonded by glycosidic linkage
  • composed of 2 or more amino sugars and an aminocyclitol (6C) ring
  • Products of various species of soil actinomycetes in genera Streptomyces and Micromonospora
  • Broad-spectrum, inhibit protein synthesis, especially useful against aerobic gram-negative rods and certain gram-positive bacteria
  • Streptomycin (produced by Streptomyces griseus) for treatment of bubonic plague, tularemia and tuberculosis

4. Tetracycline

  • broad-spectrum antibiotics that inhibit almost all gram-positive and gram-negative bacteria
  • the basic structure consists of a naphthacene ring system
  • protein synthesis inhibitor
  • Doxycycline and Minocycline are oral drugs taken for STDs, Lyme disease, typhus and Rocky Mountain spotted fever

5. Chloramphenicol

  • Isolated from Streptomyces venezuelae
  • Potent broad-spectrum drug with unique nitrobenzene structure
  • Blocks peptide bond formation
  • Very toxic and restricted uses can cause irreversible damage to bone marrow
  • Treatment for typhoid fever, brain abscesses, rickettsial and chlamydial infections

6. Bacillus antibiotics

  • Bacitracin: narrow-spectrum peptide produced by B. subtilis
  • Polymyxin: narrow-spectrum peptide with the fatty acid component, detergent activity
  • Polymyxin for treatment of drug-resistant Pseudomonas aeruginosa and urinary tract infections

7. New classes of antibiotics

  • Fosfomycin tromethamine: a phosphoric acid effective as an alternative treatment for urinary tract infection
  • Synercid: effective against Staphylococcus and Enterococcus that cause endocarditis and surgical infections

8. Synthetic antimicrobial drugs

  • Sulfonamides (sulfa drugs)- the first synthetic antimicrobial drugs
  • Sulfanilamide-selectively toxic in bacteria
  • Sulfisoxazole for treatment of shigellosis, urinary tract infections, and protozoan infections
  • Isoniazid used with rifampicin to treat tuberculosis
  • Isoniazid effective only against Mycobacterium and it interferes with the synthesis of mycolic acid
  • Fluoroquinolones such as ciprofloxacin are widely used in the beef and poultry industries for the prevention and treatment of respiratory diseases in animals
  • Ciprofloxacin is also a choice for treating anthrax

Bacteriostatic vs Bactericidal

Bacteriostatic agents:  inhibit growth but don’t kill the bacteria. They rely on the body defenses to clear the infection. A bacteriostatic agent alone can never completely eliminate the pathogenic bacteria from the body’s tissues.

  • Examples: Macrolides (clarithromycin), Tetracyclines, Lincosamides (Clindamycin), Fusidic acid, Chloramphenicol, Sulfamethoxazole, Oxazolidinones

Bactericidal agents: kills bacteria. Bactericidal agents are preferable especially if the body has trouble clearing bacteria.

  • Examples: β-lactams, Metronidazole, Rifampicin, Aminoglycosides, Quinolones, Polymyxins, Glycopeptides, Linezolid, Lipopeptides (Daptomycin), Tigecycline

Evolution of Resistance to Anti-Infective Agents

Resistance to anti-infective agents is genetically determined by the resistance genes. The resistance genes might evolve in bacteria that shared the natural habitat of the antibiotic producers. They secure their own ecological niche in the presence of the producers by means of the characteristic of resistance. At a later point in the evolutionary process, such genes have accidentally, and rarely, found their way into the genetic material of human pathogen bacteria. Hence, when new antibiotic substances come to be used for therapeutic purposes, there are always a small number of bacteria that already show resistance to them.

It is limited for us to predict and combat the evolution of antibiotic resistance in pathogens as resistance evolution involves a complex interaction between the specific drugs, bacterial genetics, and both natural and treatment ecology. In 2012, the World Health Organization (WHO) published The Evolving Threat of Antimicrobial Resistance-Options for Action by proposing a combination of interventions that include strengthening health systems and surveillance, improving the use of antimicrobials in hospital and community, infection prevention and control, and encouraging the development of appropriate new drugs and vaccines. According to the estimation by the Center for Disease Control and Prevention (CDC), more than two million people are affected with antibiotic-resistance infections every year, with at least a number of 23000 dying as a result of the infection.

Several fields of modern medicine depending on the availability of effective antimicrobial drugs included chemotherapy for cancer treatment, organ transplantation, hip replacement surgery, intensive care for pre-term newborns and many other events that could not be performed without effective antibiotics. Instead, the infections caused by multidrug-resistant bacterial strains contribute to the morbidity and mortality of patients during these procedures.

The lack of basic knowledge on these topics is one of the main reasons that there has been so little significant achievement in the effective prevention and control of resistance development. Given the increasing awareness about the resistance of antimicrobial drugs, it should now be possible to have early warnings of this crisis and we should take action to solve this problem in a proactive manner.



Antimicrobial Drugs and Their Evolution of Resistance

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