Chapter 18
Antimicrobial Drugs
18.1 The History and Properties of Antimicrobial Agents
• The History of Chemotherapy Originated with Paul Ehrlich
• Ehrlich originated the concept of selective toxicity
• Ehrlich and Sahachiro Hata discovered the effectiveness of arsphenamine
(Salvarsan) against the syphilis spirochete
• Prontosil was a red dye found to inhibit some gram-positive bacterial
species
• Alexander Fleming’s Serendipitous Discovery of Penicillin Ushered in the Era of
Antibiotics
• Penicillium mold produces a substance that kills gram-positive bacteria
• Antimicrobial Agents Have a Number of Important Properties
• Synthetic agents are made in a pharmaceutical lab
• Antibiotics are products of or derived from living microorganisms
• Semisynthetic drugs include synthetic and antibiotic elements
• Selective toxicity means that a drug should harm the pathogen but not the host
• The toxic dose of a drug is the concentration causing harm to the host
• The therapeutic dose is the concentration eliminating pathogens in the host
• Together, the toxic and therapeutic doses are used to formulate the
chemotherapeutic index
• Drugs have a range of pathogens on which they will work (antimicrobial
spectrum)
• Broad-spectrum drugs affect many taxonomic groups
• Narrow-spectrum drugs affect only a few pathogens
18.2 The Synthetic Antibacterial Agents
• Sulfanilamide and Other Sulfonamides Target Specific Metabolic Reactions
• Sulfonamides out compete essential folic acid components for binding
sites in a bacterial enzyme
• They prevent nucleic acid synthesis and DNA replication
• Other Synthetic Antimicrobials Have Additional Bacterial Cell Targets
• Isoniazid interferes with cell wall synthesis in species of Mycobacterium
• Quinolones block DNA synthesis in bacteria
18.3 The Beta-Lactam Family of Antibiotics
• Penicillin Has Remained the Most Widely Used Antibiotic
• Penicillins are active against many gram-positive and some gram-negative
bacteria
• They interfere with cell wall synthesis, causing the cell to burst
• Some individuals experience an anaphylactic allergic reaction
• Many penicillin-resistant species produce beta-lactamases that inactivate
penicillin
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Numerous semisynthetic penicillins have been developed
Other Beta-Lactam Antibiotics Also Inhibit Cell Wall Synthesis
• Cephalosporins are broader spectrum alternatives to penicillins
• Monobactams are active against aerobic, gram-negative rods
• Carbapenems are broad spectum drugs
• For example, Imipenem
18.4 Other Bacterially Produced Antibiotics
• Vancomycin Also Inhibits Cell Wall Synthesis
• It is effective against gram-positive bacteria such as staphylococci
• Side effects include damage to the ears and kidneys
• Polypeptide Antibiotics Affect the Cell Membrane
• Bacitracin interferes with transport of cell wall precursors through the
membrane
• It is toxic internally, so is used topically
• Polymyxins increase membrane permeability of gram-negative rods
• Many Antibiotics Affect Protein Synthesis
• Aminoglycosides attach to bacterial ribosomes, blocking transcription
• Streptomycin is sometimes used in tuberculosis cases
• Gentamicin is used against gram-negative infections in the urinary
tract
• Neomycin is used for intestinal infections and as an ointment
• Kanamycin is used against gram-negative bacteria in
wound tissue
• Chloramphenicol is used against a wide variety of bacteria and some rickettsiae
and fungi
• It is reserved for serious infections like
– meningitis
– cholera
– typhoid and typhus fevers
– Rocky Mountain spotted fever
• Severe side effects include aplastic anemia and gray syndrome
• Tetracyclines have a similar antimicrobial range to chloramphenicol
• They have a benzene ring formation
• They can destroy intestinal microbiota and cause staining of the teeth
• The macrolide erythromycin is used against gram-positive bacteria
• Clindamycin is a semisynthetic drug used against penicillin-resistant bacteria
• Pseudomembranous colitis can occur if microbiota are killed, allowing
Clostridium difficile to flourish
• Streptogramins are effective against gram-positive bacteria
• Oxazolidinones are effective against gram-positive bacteria, including multidrugresistant Staphylococcus aureus
• Some Antibiotics Inhibit Nucleic Acid Synthesis
• Rifampin interferes with RNA synthesis
• It is effective against tuberculosis, leprosy, and meningitis
• It can cause liver damage
18.5 Antifungal and Antiparasitic Agents
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Several Classes of Antifungal Drugs Cause Membrane Damage
• Polyenes bind to ergosterol in fungal plasma membranes, causing contents
to leak out
• Nystatin is used against Candida albicans infections in the
intestines or vagina
• Amphotericin B is used against serious systemic fungal infections
• Imidiazoles inhibit an enzyme needed to form ergosterol in the fungal
plasma membrane
• They are used topically and/or internally for cutaneous and
systemic infections, respectively
• Echinocandins inhibit fungal cell wall synthesis
• Caspofungin is used to treat invasive candidiasis and aspergillosis
• Flucytosine interrupts nucleic acid synthesis
• It is active against strains of Candida and Cryptococcus
• Griseofulvin binds to microtubules, inhibiting mitosis
• It is used against ringworm and athlete’s foot
• The Goal of Antiprotozoal Agents Is to Eradicate the Parasite
• Aminoquinolines are antimalarial drugs that accumulate in parasitized red
blood cells
• They interfere with the parasite’s ability to break down and digest
hemoglobin
• Sulfonamides block folic acid synthesis as they do for bacteria
• Nitroimidazoles interfere with DNA synthesis
• They are used to treat
• amebiasis
• giardiasis
• trichomoniasis
• A derivative of arsenic is used against African trypanosomiasis
• A derivative of antimony is used against leishmaniasis (as is pentamidine)
• Artemisinin destroys malarial parasites by releasing free radicals in red blood
cells
• Antihelminthic Agents Are Targeted at Nondividing Helminths
• Praziqyantel changes membrane permeability in cestodes and trematodes
• This causes contraction and paralysis in the parasite
• Mebendazole:
• inhibits nutrient uptake in worms in the host intestine
• disrupts microtubules and cell division
• Avermectins cause paralysis in a number of roundworms
18.6 Antibiotic Assays and Resistance
• There Are Several Antibiotic Susceptibility Assays
• The tube dilution method determines the minimum inhibitory
concentration
• The agar disk diffusion method involves different antibiotics diffusing
from paper disks in a bacterial colony
• There Are Four Mechanisms of Antibiotic Resistance
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Many species of bacteria have evolved resistance to certain antibiotics and
synthetic agents
• The evolution of strains of S. aureus resistant to multiple drugs is
particularly alarming
1. Resistance to sulfonamides may develop if the bacterial enzyme changes or
if the bacteria evolves an alternate metabolic pathway
2. Bacteria may evolve the ability to enzymatically inactivate an antibiotic
3. Bacteria may evolve the ability to prevent drug entry into the cytoplasm or
to pump the drug out of the cytoplasm
4. Bacteria can evolve changes in drug targets like ribosomes or enzymes
involved in replication
Antibiotic Resistance Is of Grave Concern in the Medical Community
• Improper or excessive use of antibiotics causes antibiotic resistance
Unnecessarily large antibiotic doses allow resistant strains to overgrow
susceptible ones
• If resistant strains spread to other patients, a superinfection occurs
Antibiotics are available over the counter in developing countries, allowing for
overuse and incorrect use
Antibiotic use is widespread in livestock feeds
• They can be transmitted to humans through meat consumption
Bacterial cells can pass resistance genes to other bacterial cells
New Approaches to Antibiotic Therapy Are Needed
• Scientists work to find new antibiotic targets in pathogens
• The lipopolysaccharide in gram-negative membranes contains
several possible targets
• Interference with DNA adenine methylase disables
– DNA structure
– replication
– repair
• Discovery of new and unique antibiotics is necessary