EXAM 4 - Part 1

Part 1: Antimicrobial Drugs and Microbial Diseases of the Skin and Eye

Narrow spectrum of microbial activity

range of different microorganism affected by an antimicrobial drug

Broad spectrum antibiotics

effective against a wide range of gram +/-

Bactericidal

antibiotics kill microbes

Bacteriostatic

prevent microbes from growing

• immune system hosts defenses like, phagocytosis and antibody production, will destroy the organism

What are the 5 core actions of microbial drugs?

• Inhibition of Cell wall Synthesis

• Inhibition of Protein Synthesis

• Inhibition of Nucleic Acid Replication and Transcription

• Injury to Plasma Membrane

• Inhibition of Essential Metabolite Synthesis

Inhibiting Cell Wall Synthesis

If damaged or process of growing, the cell wall can’t repair because penicillin inhibits the bacteria to build a new cell wall.

What is the inhibitor of cell wall synthesis?

Penicillin

• Prevents the synthesis of intact peptidoglycan

• Penicillinases are bacterial enzymes that destroy natural penicillins

Outcomes:

• Cell wall is greatly weakened

• lysis

• Only actively growing cells are affected antibiotics

What drug was developed to defeat Penicillinase-Resistant Penicillins?

Methicillin was introduced to combat penicillinases, but resistance quickly emerged via Methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin has since been discontinued in the U.S.

What other microbial drugs inhibit Cell Wall Synthesis?

• Carbapenems: Broad-spectrum antibiotics that inhibit cell wall synthesis.

• Cephalosporins: Inhibit cell wall synthesis

• Bacitracin (Polypeptides)

• Vancomycin

What is Vancomycin?

Inhibit cell wall synthesis

• Can be used to kill penicillinase producing staphylococci

Important in addressing the problem of MRSA

• A last line of antibiotic defense for Staphylococcus aureus treatment

• Has lead to the appearance of vancomycin-resistant enterococci (VRE), common in hospital settings

What is Bacitracin?

Inhibit cell wall synthesis; mostly in gram positive bacteria (such as staphylococci and streptococci)

• It interferes with the linear strands of peptidoglycan at an earlier stage than penicillin.

• Due to toxicity, it is restricted to topical application for superficial infections.

Inhibiting Protein Synthesis

Antibiotics can target the 70s ribosomes in prokaryotes and not target the 80s ribosomes in eukaryotes

(difference in structure allows for selectivity)

What are the inhibitors for Protein Synthesis?

• Chloramphenicol

• Streptomycin

• Tetracyclines

What is Streptomycin?

Changes the shape of the 30S subunit, causing the genetic code on mRNA to be read incorrectly during translation.

What is Chloramphenicol?

Binds to the 50S ribosomal subunit and inhibits peptide bond formation.

• It is inexpensive to make and broad-spectrum, but it can suppress host bone marrow activity.

What are Tetracyclines?

Interfere with the attachment of tRNA carrying amino acids to the mRNA-ribosome complex

• Produced by Streptomyces spp.

• Prevents polypeptide elongation.

• Effective against Gram-positive and Gram-negative bacteria, as well rickettsias and chlamydias which are harder to treat.

Inhibition of Nucleic Acid Synthesis

Antibiotics can interfere with DNA replication and transcription

What are the inhibitors of Nucleic Acid Synthesis?

• Rifamycin

• Quinolones and Fluoroquinolones

What is Rifamycin?

Inhibits RNA polymerase to halt mRNA synthesis.

• prominently used to treat tuberculosis.

What are Quinolones and Fluoroquinolones?

Inhibit DNA gyrase

(the unwinding enzyme required for replication)

• Commonly prescribed for urinary tract infections

Injuring the Plasma Membrane

Antibiotics can cause changes in the permeability of the plasma membrane, perforating holes

• Some antifungal drugs are effective against a range of fungal disease

• Combine with sterols in the fungal plasma membrane

What drugs causes injury to the Plasma Membrane in Fungi?

• Amphotericin B

• Azoles

• Bacitracin?: inhibit cell wall synthesis

However, these drugs are not effective against bacteria because bacteria lack sterols. It’s effective in yeast.

What is Amphotericin B?

Targets ergosterol in the fungal plasma membrane, causing leakage.

Effective against systemic yeast and fungal conditions.

What is Azoles?

Interfere with sterol synthesis; used for cutaneous and systemic mycoses.

What drugs causes injury to the Plasma Membrane in bacteria?

• Polymyxin B

• Polymyxin E (Colistin)

What is Polymyxin B?

A bactericidal antibiotic effective against Gram-negative bacteria.

• Alters membrane permeability and used primarily in topical treatments.

What is Polymyxin E (Colistin)?

Used to treat antibiotic-resistant ventilator-associated pneumonia

• VAP was caused by G-colistin-resistant, E.coli found in two patients in the U.S. in 2016

How does Inhibiting the Synthesis of Essential Metabolites work?

1. Para-aminobenzoic acid (PABA) is the substrate required by bacteria to synthesize folic acid (a coenzyme for nitrogenous base production)

2. Sulfanilamide (Sulfa Drug) acts as a competitive inhibitor that blocks PABA from binding to the enzyme's active site.

   • Often combined with trimethoprim (SXT), it acts as a bacteriostatic drug configuration to halt bacterial growth.

What is Sulfanilamide (Sulfa Drug)?

Acts as a competitive inhibitor that blocks PABA from binding to the enzyme's active site.

• Often combined with trimethoprim (SXT), it acts as a bacteriostatic drug configuration to halt bacterial growth.

What is Echinocandins?

Interfere with fungal cell wall synthesis

What agent inhibits Nucleic Acid?

Flucytosine

What is Flucytosine?

Interferes with biosynthesis of RNA and protein synthesis (cytosine analog)

Fungal cells can convert flucytosine into 5-fluorouracil and is incorporated into RNA

(mammalian cells lack the enzyme to convert the drug)

• Most effective against Candida and Cryptococcus

What is Griseofulvin?

Interferes with eukaryotic cell division

• Used to primarily treat skin infections caused by fungi

• Drug binds selectively to the keratin found in the skin, hair follicles and nails

• Inhibits fungal reproduction from undergoing binary fission

What agents affect fungal cell wall?

Echinocandin groups inhibit the biosynthesis of glucans

• results in an incomplete cell wall and lysis

• caspofungin is used to treat systemic Aspergillus and Candida infections

What is the purpose of Antiviral Drugs for HIV?

Prevents the virus (HIV) from gaining access into cell and fusing with mammalian cell

How does the Antiviral drug for HIV work?

Entry inhibitors and fusion inhibitors bind to the HIV attachment and receptor sites

• Inhibitors of viral enzymes: Acyclovir and Zidovudine inhibit RNA or RNA synthesis

What are Entry Inhibitors?

Drugs that block absorption and penetration

• Example: HIV treatment, targets the receptors that HIV uses to bind to the cell before entry

  • receptor mediated endocytosis (lock & key)

What are Fusion Inhibitors?

Block fusion of the virus

• Example: Entry of HIV into the cell can be blocked by fusion inhibitors

Antiviral Drug for HIV

Zidovudine

Antiviral drug for HSV, Shingles, and Chickenpox

Acyclovir

Antiviral drug for Influenza (flu)

Inhibitors of viral enzymes

• Alpha interferons inhibit the spread of viruses to new cells

An example of a test guide to chemotherapy

Disk Diffusion Methods

Disk Diffusion Methods

Filter paper disks placed on agar with known concentrations of chemotherapeutic agents

Zone of inhibition determines effectiveness

• During incubation the chemotherapeutic agents diffuse from the disks into the agar

• The farther the agent diffuses from the disk, the lower its concentration

• Larger the zone = greater/more effective drug is

Examples of Antihelminthic Drugs

• Mebendazole

• Albendazole

• Ivermectin

What is Mebendazole and Albendazole?

Broad-spectrum anthelmintics with few side effects that interfere with the parasite's nutrient absorption.

What is Ivermectin?

Used extensively in the livestock industry

• Induces paralysis and death of the helminth without harming the mammalian host.

Resistance to Antimicrobial Drugs

Many bacterial diseases are treatable with antibiotics, however…

• Antibiotic resistance has doubled over the past 20 years.

• Superbugs are bacteria resistant to multiple classes of antibiotics.

• Resistance genes are regularly transferred horizontally between bacteria via conjugation pili.

Common Mechanisms of Resistance:

1. Enzymatic destruction or inactivation of the drug (e.g., penicillinase).

2. Prevention of penetration to the target site within the microbe.

3. Cellular or metabolic changes at the target sites.

4. Altering the specific target site of the antibiotic.

Minimizing Resistance: Administering antibiotics in correct concentrations and appropriate dosages, and limiting prescriptions strictly to cases where they are absolutely necessary.

Antibiotic Safety: What is Risk vs. Benefit?

Antibiotic must always be evaluated.

• Side effects include hypersensitivity reactions, neutralizing the efficacy of contraceptive pills, or toxicity risks in pregnant women.

Effects of Combination Drugs: What is Synergistic Effects?

The combination of two drugs is more effective than either alone.

• Demonstrating a larger combined zone of inhibition (e.g., amoxicillin-clavulanic acid paired with aztreonam).

Effects of Combination Drugs: What is Antagonistic Effects?

The combination makes both drugs less effective than when taken individually.

What is the Future of Chemotherapeutic Agents?

• New options include antimicrobial peptides, bacteriocins, and bacteriophages (viruses that specifically attack bacteria).

• New paradigms aim to target virulence factors rather than blocking cell growth directly.

  • Ex: instead of targeting the cholera bacillus, drug might target the cholera toxin

  • neutralizing or destroying target products (chemical, toxins, and/or enzymes)

Vesicles

• Small, fluid-filled lesions

• Fluid can be clear, yellow, or mixed with blood

Bullae

Larger vesicles

Macules

Flat, reddened lesions

• Red splotches

Pustules

Flat, reddened lesions when contain pus

Papules

raised lesions

• solid

Exanthems

Skin rash that arises from diseased conditions

• Can be viral

• Caused by enteroviruses, adenovirus, chicken pox, measles, rubella and mononucleosis

Enanthems

Skin rash localized to the mucous membrane

• caused by toxins, drugs, or microorganisms

• usually occurs in children

Folliculitis

An infection of hair follicles

• Pimples

Boil

More serious hair follicle infection (a type of abscess)

• Localized region of pus surrounded by inflamed tissue

Carbuncle

A hard, round deep inflammation of tissue under the skin

• Abscess

• Typically infected with Staphylococcus bacteria

Sty

Infected eyelash follicle

What are Staphylococcal Skin Infections?

Gram-positive, spherical (cocci) bacteria

Clinically divided based on their production of coagulase, an enzyme that clots fibrin in blood.

• coagulase positive: solid

• coagulase negative: liquid/runny

As they grow, they secrete virulence factors such as toxins and enzymes. They are associated with diseases like sore throats, otitis media (ear infections), meningitis (inflammation of meninges), and pneumonia.

Staphylococcus epidermidis

Coagulase-negative (Liquid/runny tube test)

Pathogenic when skin barrier is broken

Staphylococcus aureus

Coagulase-positive (Solid)

Permanent resident of the nasal passages of 20-30% of the population

• Stimulates a vigorous inflammatory response

  • Genome is larger, allowing for more virulent factors

• High toxin production

  • Most strains secrete a protein that blocks chemotaxis of neutrophils to infection site thereby blocking the host's ability to respond to infections.

Impetigo

Highly contagious skin infection, can be spread by direct contact

• Transmission: Spread to surrounding tissue, called autoinoculation

Causative agent for Impetigo

Mostly Staphylococci, but can also be caused by Streptococcus pyogenes.

What is Bullous impetigo?

Exfoliative toxin A remains localized and causes bullous impetigo, whereas exfoliative toxin B circulates to distant sites (associated with scalded skin syndrome).

Causative agent for Bullous impetigo

Staphylococcal toxins

What are the three types of Streptococcal Hemolysis?

• Alpha (α)-hemolysis: Partial digestion/hemolysis of red blood cells.

• Beta (β)-hemolysis: Complete digestion/hemolysis of red blood cells; closely associated with human disease.

• Gamma (γ)-hemolysis: Non-hemolytic.

What is Alpha (α)-hemolysis

Partial digestion/hemolysis of red blood cells.

What is Beta (β)-hemolysis?

Complete digestion/hemolysis of red blood cells; closely associated with human disease.

What is Gamma (γ)-hemolysis

Non-hemolytic

Causative agent for Group A Streptococci (GAS) infection

Streptococcus pyogenes

What is Group A Streptococci (GAS)?

Beta hemolytic associated with human disease

• Further differentiated into Groups A and T

• Exotoxins produced by certain streptococcal M-proteins

What are the virulence factors of GAS?

M protein

Hyaluronic acid capsule

M-Protein function in GAS

• Positioned external to the cell wall as a fuzzy layer on fimbriae.

• Helps the bacteria adhere to surfaces, colonize, avoid phagocytosis, and prevent the activation of the complement system.

What is Hyaluronic Acid Capsule function in GAS?

• Helps the organism avoid phagocytosis.

• Highly pathogenic strains have a heavy mucoid appearance on Blood Agar plates because hyaluronic acid closely resembles human connective tissue.

What enzymes does GAS produce to promote infection?

• Streptokinases

• Hyaluronidase

• Deoxyribonuclease

What is Streptokinases

Dissolve blood clots.

What is Hyaluronidase

Dissolves hyaluronic acid in connective tissue.

What is Deoxyribonuclease

Degrades DNA.

What is Erysipelas?

Causative agent infects dermal layer of skin

• Erupts into reddish patches

• Can progress to local tissue destruction

• Usually first appears on face

Causative agent for Erysipelas

Streptococcus pyogenes

Treatment for Erysipelas

Sensitive/respond to cephalosporin

What is Necrotizing Fasciitis?

Caused by minor breaks in skin, destroys tissue rapidly

• Early symptoms are often unrecognized, delaying diagnosis and treatment

Causative agent for Necrotizing Fasciitis

Group A streptococci

Treatment for Necrotizing Fasciitis

broad spectrum antibiotics

Infections by Pseudomonads

• widespread in soil and water

• can survive in any moist environment

Treatment: resistant to many antibiotics and disinfectants

Causative agent for Pseudomonas dermatitis and Pseudomonas aeruginosa

Pseudomonads

• Aerobic gram-negative rods

What is Pseudomonas dermatitis

Associated with swimming pools, saunas, and hot tubs

• When lots of people use them, alkalinity rises, and chlorine becomes less effective

Infection by Pseudomonas dermatitis

Otitis externa “swimmer’s ear”

• infection of external ear canal leading to the eardrum

What is Pseudomonas aeruginosa?

• Cause of hospital-associated infections of indwelling medical tubes or devices

• Can grow in flower vases, mop water, and dilute disinfectants in hospitals

• Opportunistic pathogen in burn patients

  • may produce blue-green pus

Pathogenicity of Pseudomonas aeruginosa

Produces an endotoxin and several exotoxins

Treatment for Pseudomonas aeruginosa

Quinolones

What is a Wart

• Produce a benign growth

• Spread by direct contact

• Incubation period of several weeks before waters appear

Treatment of a Wart

• cold liquid nitrogen

• dry them with electrical current

• Burn with acids

What is Smallpox?

Transmitted by the respiratory route, virus can move to the skin via the bloodstream

80% of Europe was infected ~ Middle Ages

• American colonist infected Native Americans

Treatment for Smallpox

Eradicated (eliminated) due to vaccinations by WHO