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Antimicrobial Agents

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Title: Antimicrobial Agents


1
Antimicrobial Agents
  • Most other drugs to be covered affect body
    systems to cure imbalance or malfunction
  • E.g. reduce inflammation, relieve pain, etc.
  • Antimicrobials used to inhibit or destroy living
    organisms which are uninvited guests
  • Drugs must harm invader without harming host
  • Notion of selective toxicity
  • Lectures will focus more on interactions between
    drug and microbe than drug and host.

2
Selective toxicity
  • The more distantly related the invader, the more
    targets available for the drug to hit
  • The less likelihood of toxic side effects.
  • Prokaryotes biochemically least similar
  • Fungi and Protozoa are eukaryotes, so more
    closely related to humans.
  • Helminths (worms) also animals
  • Viruses use our own cell machinery
  • Cancer cells ARE our cells.

3
History of Antimicrobial Therapy
  • 1909 Paul Ehrlich
  • Differential staining of tissue, bacteria
  • Search for magic bullet that would attack
    bacterial structures, not ours.
  • Developed salvarsan, arsenic derivative used
    against syphilis.

http//www.chemheritage.org/EducationalServices/ph
arm/antibiot/activity/stain/salvarsa.gif
4
Timeline
  • 1929 Penicillin discovered by Alexander Fleming
  • Messy lab, cool damp weather, luck
  • 1940 Florey and Chain mass produce penicillin for
    war time use, becomes available to the public.
  • 1935 Sulfa drugs discovered
  • 1943 Streptomycin discovered
  • Western civilization fundamentally changed

5
Historical distinctions
  • Antibiotics substances produced by organisms
    that have inhibitory effects on other organisms.
  • Penicillin, streptomycin
  • Synthetic drugs produced in a lab.
  • Salvarsan, sulfa drugs
  • Nowadays, most antimicrobials are semi-synthetic
  • Chemically modified versions of natural products
  • Distinction between antibiotics and synthetic
    drugs slowly being abandoned.

6
Synthetics vs. Antibiotics
  • Antibiotics generally have a lower MIC
  • Minimum inhibitory concentration
  • Effective a lower doses
  • Better therapeutic index
  • Safer larger quantity must be administered
    before harmful side effects occur.

e.g. Ti LD50 / ED50
7
Where do antibiotics come from?
  • Soil dwelling organisms
  • Several species of fungi including Penicillium
    and Cephalosporium
  • E.g. penicillin, cephalosporin
  • Species of actinomycetes, Gram positive
    filamentous bacteria
  • Many from species of Streptomyces
  • Also from Bacillus, Gram positive spore formers
  • A few from myxobacteria, Gram negative bacteria
  • New sources explored plants, herps, fish

8
Antibiotics are common in nature
  • Many are discovered every year, but not all are
    useful
  • May belong to previously recognized family, so
    not really new
  • Toxicity to host makes them unusable
  • They may have poor chemical properties
  • Insoluble, unstable, rapidly metabolized
  • No longer effective against resistant organisms

9
What and why
  • Antibiotics are secondary metabolites
  • Substances not essential for the growth of the
    organism
  • Typically produced at onset of stationary phase
  • When growth slows down
  • Production inhibited by presence of nutrients
  • Why do microbes make them?
  • No one is sure
  • Habitat guarding prevents outsiders from
    establishing themselves when residents inhibited

10
Bacteriostatic vs. Bactericidal
  • Antibiotics differ by mode of action
  • Bacteriostatic compounds inhibit the growth of
    bacteria
  • Holds invaders in check host immune system does
    the killing
  • Bactericidal compounds directly kill the bacteria
  • Location and severity of infection affect choice
    of antibiotic
  • E.g. CNS infection calls for bactericidal
    treatment.

11
Antibacterial agents
  • There are 5 principle targets for antimicrobial
    agents to work against bacterial cells
  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Attack on cell membranes
  • Disruption of nucleic acid synthesis
  • Interference with metabolism

12
Review and Overview of Bacterial Targets
  • Bacterial cell walls
  • Except for Mycoplasma and relatives, all bacteria
    of the Domain Eubacteria possess peptidoglycan
  • Peptidoglycan provides shape and structural
    support to bacterial cells
  • Bacterial cytoplasm is generally hypertonic
    compared to their environment
  • Net flow of water into cell
  • Wall under high osmotic pressure

13
Cell walls continued
  • Chemical structure of peptidoglycan contributes
    to its function
  • Polysaccharide chains composed of 2 alternating
    sugars, N-acetylglucosamine (NAG) and
    N-acetylmuramic acid (NAM)
  • Cross-linked in 3 dimensions with amino acid
    chains
  • A seamless, bag-like molecule which resists
    osmotic pressure
  • A breach in peptidoglycan endangers the bacterium

14
Glycan chains cross-linked with amino acids
  • G- and G vary w/ DAP vs. lysine and at the
    interbridge.
  • Note the presence of unusual D amino acids.
  • Peptides attached to NAM.

15
Peptidoglycan is a 3D molecule
Cross links are both horizontal and vertical
between glycan chains stacked atop one another.
http//www.sp.uconn.edu/terry/images/other/peptid
oglycan.gif http//www.alps.com.tw/cht/img/anti-a
llergy_002.jpg
16
There is no molecule similar to peptidoglycan in
humans, making drugs that target cell wall
synthesis very selective in their toxicity
against bacteria.
17
Gram positive Gram Negative
  • Gram positive bacteria have a thick cell wall
  • Peptidoglycan directly accessible from
    environment
  • Gram negative bacteria have a different wall
  • Thin layer of peptidoglycan
  • Surrounded by an outer membrane composed of
    lipopolysaccharide, phospholipids, and proteins
  • OM is a barrier to diffusion of molecules
    including many antibiotics
  • Only some antibiotics are that hydrophobic
  • Porins allow passage of only some antibiotics

18
Gram negative cell structure
19
Ribosomes site of protein synthesis
  • Prokaryotic ribosomes are 70S
  • Large subunit 50 S
  • 33 polypeptides, 5S RNA, 23 S RNA
  • Small subunit 30 S
  • 21 polypeptides, 16S RNA
  • Eukaryotic are 80S Large subunit 60 S
  • 50 polypeptides, 5S, 5.8S, and 28S RNA
  • Small subunit 40S
  • 33 polypeptides, 18S RNA

20
Differences in structure between prokaryotic and
eukaryotic ribosomes make antibiotics that target
protein synthesis fairly selectively toxic
against bacteria.
21
Other Targets
  • Bacterial DNA is negatively supercoiled
  • Supercoiling is maintained by gyrase, a type II
    topoisomerase.
  • Inhibition of gyrase and type IV topoisomerase
    interferes with DNA replication, causes cell
    death
  • Eukaryotic topoisomerases differ in structure
  • Bacterial cell membranes are essentially the same
    in structure as those of eukaryotes
  • Antibiotics also affect Gram neg. cell walls
  • Anti-membrane drugs are less selectively toxic
    than other antibiotics

22
Other Targets-2
  • Metabolic inhibitors
  • Mostly target the folic acid synthesis pathway
  • Many bacteria can and do synthesize a large
    proportion of needed cofactors
  • Humans require folic acid in the diet (a
    vitamin), thus folic acid synthesizing enzymes
    are not an available target in humans
  • Selectively toxic

23
Drug selection
  • Identity of infectious agent
  • Many infections viral, antibiotic administration
    is a dangerous waste.
  • Identification of bacterium provides rational
    basis for choice
  • Administration depends on severity of situation
  • Choice of drug influenced by location of
    infection
  • Certain bacteria are more likely at certain
    anatomical sites, directing blind choice
  • Not all drugs reach compartments equally

24
Spectrum
  • When specific testing is not done or delayed,
    antibiotic with a broad spectrum is administered
  • Broad spectrum antibiotics can penetrate Gram
    outer membranes, resist inactivation, etc.
  • Shotgun better chance of inhibiting pathogen
  • Downsides
  • Normal microbiota found in ecological balance
  • Death of normal microbiota results in overgrowth
    of native, resistant bacteria (endogenous
    infection) or allows invasion by outside
    opportunists.

25
Drug administration
  • Antibiotics administered oral, i.v., i.m.
  • Same caveats apply, i.e. acid instability,
    delayed absorption with food for oral
  • i.v. gives higher, quicker concentrations,
    reaches more compartments with sufficient dose
    quickly

26
Problem sites
  • Endocarditis fibrin from inflammation
  • CSF because of blood-brain barrier
  • Osteomyelitis
  • Artificial joints, valves
  • biofilms make it difficult for drug to reach
    target
  • Abscesses inflammatory barrier restricts access
    also bacteria stop growing
  • Intracellular infections
  • Penetration into host cells, not just microbe

27
Host factors and toxicity
  • Antibiotics have been so successful because of
    their selective toxicity
  • But any substance that has a biological effect
    will have a biological side effect
  • Allergies and intolerance
  • Immediate and delayed type hypersensitivities
    when drug acts as a hapten
  • Intolerance e.g. erythromycin makes me puke.
  • Age renal function, development, type of pathogen

28
Host factors and toxicity-2
  • Renal
  • Many antibiotics cleared through renal action, so
    renal function affects dose, choice.
  • Liver Good hepatic function needed for
    metabolism of some antibiotics
  • Pregnancy
  • Beware of developmental effects, teratogenesis
  • Host defenses
  • Influences choice of bactericidal vs.
    bacteriostatic
  • Genetic background, metabolic factors

29
Combination therapy
  • Generally frowned on by drug people
  • Some valuable reasons why combination therapy is
    used
  • Synergistic effects between two drugs
  • Polymicrobial infections, e.g. abdominal injuries
  • Avoid or circumvent microbial resistance

30
Antibiotic resistance
  • Inherent Outer membrane of Gram negative
    bacteria, wall-less bacteria.
  • Mutations change in transport protein, ribosome,
    enzyme, etc. Normally harmful mutations are
    selected FOR in the presence of antibiotic.
  • Plasmids through conjugation, genetic
    information allowing cell to overcome drug.

http//www.mun.ca/biochem/courses/3107/ images/Str
yer/Stryer_F32-13.jpg
31
Mechanisms of drug resistance
  • Alteration of target active site of enzyme
    changes, ribosome changes.
  • Alteration of membrane permeability transport
    protein changes, drug no longer enters drug that
    does enter is actively pumped out.
  • Enzymatic destruction of drug penicillinases
    (beta lactamases)
  • End around inhibitor bacteria learns to use
    new metabolic pathway, drug no longer effective.
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