BIOL 273 Mod-11

Disinfection

killing/inactivating microbes that cause disease

Sterilization

destroying all live microbes, spores, viruses

Disinfectant

can be used on inanimate objects + surfaces but it’s too toxic to the body

Antispectics

can be used on living body tissues (e.g. wound)

Chemical methods

• heavy metals

• 70% alcohol

• aldehydes

• halogens

• hydrogen peroxide

• quaternary ammonium compounds

• salt

• ethylene oxide gas

Physical methods

• physical removal

• radiation (sterilization); ex: x-rays, gamma rays

• radiation; ex: microwaves

• low temp. control

• heat; ex: dry heat (oven)

• heat (sterilization); ex: autoclaving

Pasteurization

reduces the # of pathogenic microbes

Oligodynamic effect

takes very few molecules of a heavy metal to kill/be toxic to microbes

Antibiotic

produced by microbes

• Alexander Fleming (1928) identified mold Penicillium excreting compound that was toxic to Staphylococcus, became the 1st antibiotic used (1941)

Selective toxicity

• antibiotics shld cause greater harm to microbes than their host

• interfere w/ essential structures/properties common in microbes but not in human cells

Therapeutic index

(TI = TD/ED) (Toxic dose/effective dose)

Antimicrobial action

bacteriostatic vs. bactericidal

Spectrum of activity

broad-spectrum vs. narrow spectrum

Effects of combinations

• antagonistic

• synergistic

• additive

Antagonistic (effects of combinations)

interfere w/ each other

Synergistic (effects of combinations)

1 medication enhances another

Additive (effects of combinations)

medications neither antagonistic/synergistic

Adverse effects

• allergic reactions

• toxic effects

• dysbiosis of normal flora

Tissue distribution, metabolism, and excretion

antimicrobials differ in behavior in body

• blood-brain barrier

• pH

• half-life

Resistance to antimicrobials

• certain bacteria have innate/intrinsic resistance

• bacteria may develop acquired resistance

Cell wall synthesis inhibitors (5 classes of antibiotics)

 β-Lactam ring

mechanism: inhibit enzymes that catalyze formation of peptide bridges between strands of peptidoglycan, disrupt cell wall synthesis, weaken cell wall → all lead to cell lysis

spectrum: Gram +

limitations: only effective against actively growing cells, usually more effective in Gram + bacteria

ex: ampicillin, methicillin, carbapenem, vancomycin (glycopeptide), bactracin (polypeptide)

Protein synthesis inhibitors (5 classes of antibiotics)

mechanism:

• exploits differences between prokaryotic (70S) & eukaryotic (80S) ribosomes; RIBOSOME SITE/COMPOSITION

• block translation

spectrum: Gram + & Gram -

limitations: some toxic due to mitochondria also having 70S ribosomes

ex: tetracyclines, aminoglycosides (streptomycin), macrolides (erythromycin), streptogramins, chloramphenicol (last resort, due to toxicity)

Nucleic acid synthesis inhibitors (5 classes of antibiotics)

mechanism: block DNA (gyrase) & RNA polymerase (transcription)

spectrum: both major classes bactericidal & broad spectrum

limitations: development of resistance

ex: fluoroquinolones, rifamycins

Metabolic pathway interference (5 classes of antibiotics)

mechanism: antimetabolites competitively bind with enzymes (molecular mimicry) rendering them inactive

spectrum: bacteriostatic & broad spectrum

ex: sulfa drugs (sulfonamides), trimethoprim

Cell membrane interference (5 classes of antibiotics)

mechanism: dmg. bacterial membranes → cause cells to leak, leading to death

spectrum: narrow spectrum

limitations: topical applications only due to toxicity

ex: daptomycin, polymyxin B

Broad-spectrum antibiotic

exhibit activity against a wide variety of Gram + and Gram - bacteria and in some cases anaerobic/atypical organisms 

ex: extended-spectrum β-lactams (including aminopenicillins, third- and fourth-generation cephalosporins, and carbapenems), tetracyclines, and fluoroquinolones

advantage: useful when the cause of infection is unknown/ mixed infections are suspected

disadvantage: their extensive activity may disrupt the normal microbiota & may increase the risk of resistance selection

Narrow-spectrum antibiotics

provided target antimicrobial activity when the pathogen is known

ex: glycopeptides and lincosamides, effective against a limited subset of bacteria, often targeting specific Gram + organisms or defined anaerobic groups

advantage: the targeted antimicrobial activity minimizes dmg. to the microbiota & potentially reduce the selective pressure for antimicrobial resistance

Impact antibiotics have on healthcare & detrimental effects of the rise in antibiotic resistance

considered the single most important medical discovery for treating infectious diseases in history, saving millions of lives since WWII

Antibiotic resistance

is when germs (bacteria, fungi) develop the ability to overcome the effect of antibiotics designed to kill them

• it doesn’t mean your body is resistance to antibiotics!

5 mechanisms of antibiotic resistance

1) enzymatc inactivation

2) alter antibiotic uptake

• membrane pump

• decrease membrane permeability

3) modify target of antibiotic

4) develop alternate metabolic pathway

Enzymatic inactivation (mechanism of antibiotic resistance)

germ develop new cell processes that avoid using the antibiotic’s target

Alter antibiotic uptake/decrease membrane permeability (mechanism of antibiotic resistance)

germs change/destroy the antibiotics w/ enzymes, proteins that break down the drug

Membrane pump (mechanism of antibiotic resistance)

germs restrict access by changing the entryways/limiting the # of entryways

Modify target of antibiotics (mechanism of antibiotic resistance)

germs change the antibiotic’s target so the drug can no longer fit and do its job

Develop alternate metabolic pathway (mechanism of antibiotic resistance)

germs get rid of antibiotics using pump

3 main factors driving rise of antibiotic resistance

1) overuse of antibiotics drive evolution of resistance

• purchasing online

• lack of regulation

2) inappropriate prescribing

• treatment indication, choice of agent, or duration of antibiotic therapy is incorrect in 30-50% of cases

3) extensive agricultural use

• 80% of antibiotics sold in the U.S. are used in animals to promote growth and prevent infections

• 90% of antibiotics given to livestock are excreted then widely dispersed through fertilizer, groundwater, and surface runoff

Alternatives to antibiotics

• vaccines

• antibodies

• bacteriophages

• fecal microbiota transplant (FMT)

• other alternative agents

Antiviral agents

relatively few effective + nontoxic antiviral agents as viruses typically utilize host enzymes for replication

5 mechanisms of action of antiviral agents

1) prevent viral entry

2) interfere w/ viral uncoating

3) interfere w/ viral nucleic acid synthesis

4) prevent genome integration

prevent assembly & released of viral particles

Prevent viral entry (mechanisms of action of antiviral agents)

interferes with binding of HIV to host cell receptors

ex: maraviroc block HIV co-receptor CCR5

interfere w/ viral uncoating (mechanisms of action of antiviral agents)

nucleic acid must separate from protein coat in order for replication to occur

• ex: rimantadine blocks Influenza A viral uncoating

Interfere w/ viral nucleic acid synthesis (mechanisms of action of antiviral agents)

• nucleoside analogs - structure similar to nucleotides

• incorporation into nucleotide chain can stop nucleotides from being added or alter base-pairing properties

ex: remdesivir for possible treatment of COVID-19; main target is NUCLEIC ACID SYNTHESIS

• Non-Nucleoside Polymerase Inhibitors

  • inhibit viral polymerases by binding to site other than nucleotide-binding site

• Non-Nucleoside Reverse Transcriptase Inhibitors

  • inhibit RT by binding to site other than nucleotide-binding site

  • often used with nucleoside analogs to treat HIV infections

Prevent genome integration (mechanisms of action of antiviral agents)

inhibits integrate in HIV - new option for treating HIV infections

Prevent assembly & release of viral particles (mechanisms of action of antiviral agents)

• inhibits enzymes needed for assembly and release

• protease inhibitors and neuraminidase inhibitors

MOST to LEAST resistant to disinfection

1) prions

2) bacterial spores

3) helminth eggs

4) mycobacteria

5) small, non enveloped viruses

6) protozoan cystic

7) fungal spores

8) gram -

9) yeast

10) gram +

11) enveloped viruses

Modern medical advances that require frequence use of antibiotics

• organ transplants

• cancer care

• surgery