8. Antimicrobial Agents and Resistance Flashcards
1
Q
What is an antimicrobial?
A
- A SELECTIVE inhibitor of microbial growth (very specific)
- Able to kill microbial cells without killing human cells
2
Q
What are the general properties of antimicrobials?
A
- Exploit the biochemical differences between microbial and mammalian cells (thus difficult for eukaryotic or viral pathogens, antimicrobial often just means antibiotic)
- Can be narrow spectrum (effective against specific bacterial species) or broad spectrum (effective against gram positive and gram negative bacteria)
- Can be:
- Natural: obtained commercially by fermentation of producer organism - most are
- Semi-synthetic: chemically modified natural products - some
- Synthetic: purely synthetic starting product - very few
3
Q
What are the two broad types of microbiological effects?
A
Static effects:
- stops the increase in viable cell numbers (limits growth)
- may cure by allowing host defence mechanisms to cope with infection
Cidal effects:
- reduce the number of viable microbial cells (kill bacteria)
- antibmicrobials may be cytocidal for one organism by cytostatic for another
4
Q
What are antimicrobial targets?
A
- Macromolecules (often enzymes) unique to the microbial cell or highly divergent from human homologues
- Metabolic processes that can be by-passed in humans but not pathogen
e. g. tetracyclines target the bacterial 30S ribosome subunit
e. g. B-lactams target the peptidoglycan cell wall assembly
5
Q
What is nosocomial bacterial pneumonia?
A
- Hospital acquired pneumonia (HAP)
- Ventilator-associated pneumonia
- First line treatment: high dose ampicillin (type of B-lactam antibiotic)- S. pneumoniae assumed
- If caused by Kribesiella pneumoniae it is more serious and difficult to treat
- K. pneumoniae can host mobile genetic elements and produce: extended spectrum beta-laminases and carbapenemase which means it is B-lactamase and carbapenem resistant
- Cannot really be treated with antibiotics: colistin and rifampicin both toxic normally poorly active against enterobacteria can be tried but not effective
6
Q
What are the peptidoglycan synthesis inhibitor class of antimicrobials?
A
- Beta-Lactam Antibiotics:
- B-lactam ring structurally resembles D-Ala-D-Ala (a peptidoglycan subunit)
- It binds to the cross-linking enzymes (penicillin binding proteins PBPs) forming a long-lived complex and thus inhibiting cross-linking of peptidoglycan in cell wall
- Under-cross linked peptidoglycan provides less support and the bacteria will lyse under osmotic pressure
- ineffective against archaea and mycoplasma because they lack peptidoglycan and intracellular bacteria because it cannot penetrate human cells
e. g. penicillins such as ampicillin and amoxycillin as well as carbapenems, cephalosporins (cefotaxime) etc. - Vancomycin:
- Bind to the terminal D-Ala-D-Ala dipeptide and inbhits transglycosylation and transpeptidation (prevents the PBPs from cross-linking)
- Bactericidal
- Effective against gram positive bacteria only
- Mostly used in infections caused by B-lactam resistant gram positive organisms e.g. MRSA and to treat C. difficile
- Resistance is acquired through coverting D-Ala to D-lactate
7
Q
How does B-lactamase-mediated resistance occur?
A
- Via B-lactamases
- Enzymes within the periplasm of gram negative bacteria (as the outer membrane will secure the enzyme)
8
Q
What are Bacterial Cell Membrane Disruptant Antimicrobials?
A
- Polymyxin E (Colistin):
- A gram negative bacteria membrane disrupter
- Binds to lipid A of LPS
- Bactericidal
- Must be injected and is mildly toxic to human cells (last resort drug for multi drug resistant bacteria)
- Resistance through LPS mutations - Daptomycin:
- Membrane disruptor for gram positive bacteria
- Binds to negative charges on phospholipids
- Binds membranes in phosphatidyl glycerol-dependent manner (resistance is through mutations in this)
- Causes membrane depolarisation
- Bactericidal
- Used for MDR Gram + bacteria
9
Q
What are Protein Synthesis Inhibitor Antimicrobials?
A
- Tend to target ribosomes (small subunit: decodes the mRNA and proofreads the incoming tRNA; and large subunit: catalyses peptide bond formation
- Aminoglycosides:
- Binds to decoding centre of ribosomes (small subunit) to introduce errors into protein sequence
- Used primarily for gram negative aerobic bacteria
- Only bactericidal protein synthesis inhibitor
e. g. streptomycin
e. g. kanamycin - Tetracyclines:
- Bind to small ribosomal subunit and prevent entry of acyl-tRNA
- broad spectrum
- bacteriostatic effect
- active against intracellular pathogens
- damage tooth enamel
e. g. doxycycline, tigecycline - Macrolides:
- Bacteriostatic
- Bind large ribosomal subunit and block elongation of peptide chain
- Long PK half-life (low dosage)
- Mostly target gram positive bacteria
- Active against intracellular pathogens e.g. mycoplasma
- multiple resistance mechanisms
e. g. erythromycin
e. g. azithromycin
10
Q
What are the Nucleic Acid Synthesis Inhibitors?
A
- Rifamycins:
- Bind to DNA dep RNA polymerase and block synthesis of mRNA
- Bactericidal
- Broad spectrum (but not effective against enterobacteria, Pseudomonas or acinebacter
- Used for mycobacterial infections - DNA replication inhibitors (Fluoroquinoles):
- Target DNA replication
- Bind to DNA gyras and topisomerase IV
- Bactericidal
- Broad spectrum
- Used for UTIs, GI tract infections, anthrax, pneumonia
e. g. ciprofloxacin
11
Q
What are Antimetabolite Antimicrobials?
A
- Usually competitive inhibitors of a natural metabolite
- Not ideal antimicrobials because if they competitively inhibit metabolites, metabolites will subsequently increase until the inhibitor is out-competed
- Antifolates:
- Interfere with folic acid metabolism
- Has to be given in combination with other microbials
- Broad spectrum
- Bacteriostatic
e. g. Trimethoprim + Sulfonamides
12
Q
What are antivirals?
Why are they difficult to make?
A
Include:
- Polymerase inhibitors
- Protease inhibitors
- Viral entry/exit inhibitors
- Resistance due to target mutation occurs
- Generally difficult to develop antivirals because most of the viral biochemical processes are conducted by the human cell - hard to inhibit without killing human cells
13
Q
What are antifungals?
Why are they difficult to make?
A
Target:
- Glucan polymers in cell wall
- Pyrimidin salvage pathways
- Ergosterol in membrane
- Difficult to develop antifungals because they are eukaryotic pathogens that have similar biochemistry to humans
14
Q
What are the general mechanisms of antimicrobial resistance?
A
- Alterations to target site
- lowered affinity for antibiotic
- protection from antibiotic binding - Altered transport
- Decreased cell wall permeability
- Active efflux - Drug inactivation:
- Beta-lactimases
- Aminoglycoside-modifying enzymes
- Chloramphenicol acetyl transferase
15
Q
What does tolerance refer to?
A
- Bacteria are still inhibited but the bacteria do not lose viability and recover after the antibiotic is not longer present
