Antimicrobial drugs and drug resistance

When are antimicrobial drugs used?

• Used when immunization has not occurred and the immune system has difficulty to eliminate infection

• Useful against bacterial infection not viral, very few antivirals are available

• These are compounds that kill or control the growth of microorganisms in the host

What kind of toxicity should drugs display

Selective toxicity or they will cause damage to the host

What’re the 2 broad categories of antimicrobial drugs?

• Synthetic

• Natural

How does a large number of antibiotics occur?

• Naturally without any real clinical use cuz of solubility

• Produced by bacteria and fungi

What’s another way antimicrobial drugs can be described?

• Based on being either bacteriostatic (inhibit from growing) or bacteriocidal(kill it) (how they work)

• Broad spectrum (affect many different types) or narrow spectrum (limited host range)

What’re some of the antibiotic targets?

• Cell wall synthesis

• Folic acid metabolism

• Cytoplasmic membrane structure and function

• DNA gyrase

• RNA elongation

• DNA directed RNA polymerase

• Protein synthesis (50S inhibitors)

• Protein synthesis (30S inhibitors)

• Protein synthesis (RNA)

• Lipid biosynthesis

What do cell wall agents do?

• Offer excellent selective toxicity

• Most widely used class of antibiotics

Explain what the beta lactation antibiotics are

• Cell wall active agent

• Largest class of cell wall active agents

• Common feature is beta-lactation ring

• Naturally occurring: produced by penicillin and Cephalosporium fungi

• Can be modified in the lab to produce semi-synthetic drugs that have a modified spectrum of activity

• Susceptible to beta lactamases which are enzymes produced by some bugs to cut and inactivate beta lactams

Explain what penicillin is and does?

• Cell wall active antimicrobial drug

• Have a narrow spectrum of activity

• Characterized by a five membered ring attached to the beta lactation component

• Target transpeptidation in gram positive bacteria

• Cannot penetrate outer membrane of gram -ve bacteria

  • Semi synthetic penicillin are modified to provide some activity against gram -ve bugs, ex: ampicillin

Explain what Cephalosporins are and what they do?

• Cell wall active antimicrobial drug

• Structurally distinct from penicillin, has SIX membered ring attached to theta lactam component

• Also target transpeptidation of peptidoglycan

• Broader spectrum activity than penicillin

• Many semi-synthetic examples

• Better resistance against beta lactamases

• Grouped into generations : 1st, 2nd etc

What’re growth factor analogs?

• They have similar structures to growth factors but dont function in the cell

  • Analogs similar to vitamins, amino acids, etc

What’re some examples of growth factor analogs?

• Sulfa drugs like sulfanilamide

  • Discovered by Gerard Domagk in the 1930s

  • Inhibit growth of bacteria by inhibiting folic acid synthesis and thus nucleic acid synthesis

  • Often used in combination with another analog called trimethoprim, The combination of this minimizes the likelihood of resistance

• Isoniazid

  • Extremely narrow spectrum cell wall active agent

  • Analog of mycolic acid component needed by mycobacterium spp

What’re some other nucleic acid synthesis inhibitors?

• Quinolones

  • Synthetic antimicrobials

  • Inhibit DNA gyrase by preventing supercoiling of DNA

  • Active against both gram -ve and gram +ve bacteria

• Ex: ciprofloxacin a fluoridated quinolone (fluoroquinolone)

  • Useful against life threatening infections

What do you use when you dont know what disease is?

Hit it with broad spectrum drug

What do protein synthesis inhibitors do?

• Target 70s ribosomes

  • Good selective toxicity

  • Some issues because human cells have 70s ribosomes in the mitochondrial matrix

What’re the 3 types of protein synthesis inhibitors?

• Aminoglycosides

• Tetracycline

• Macrolides

Explain aminoglycosides

• Bind to 30s subunit of 70s ribosomes

• Block translation

• Narrow spectrum which is useful against gram negative bugs

• Often used as a last resort drug

• Ex: Streptomycin, gentamycin, neomycin

Explain tetracycline

• Broad spectrum

• Produced by the species of the streptomyces genus

• Bind to 30s subunit

• Consists of both natural and modified semisynthetic drugs

• Binds to calcium damaging teeth and bone so shouldn’t be used in children and pregnant women

• Used in veterinary medicine and to promote animal growth

  • Creates problem with resistance

Explain macrolides

• Broad spectrum of activity

• Bind to the 50s ribosomal subunit

• Only inhibits translation of some proteins

• Some proteins are preferential translated and others are not

  • Creates a detrimental protein imbalance inside the cell

• Useful to treat infection in patients with allergies to beta lactam antibiotics

• Ex: erythromycin and azithromycin

  • Produced by Streptomyces spp.

What’re the different types of novel antibiotics?

• Daptomycin

• Platensimycin

Explain Daptomycin

• Novel antibiotic

• Produced by streptomyces spp

• Cyclic lipopeptide

  • Active against gram positives

  • Pathogenic Staphylococcal spp and streptococcal spp

• Forms pores in the plasma membrane causing depolarization

  • Cell cant synthesize necessary biomolecules

  • Cell death occurs

• Resistance can occur when bacteria alter plasma membrane composition

Explain platensimycin

• Novel antibiotics

• Inhibits fatty acid biosynthesis

• Produced by streptomyces platensis

• Broad spectrum of activity against gram positive bacteria

• Useful against important resistant gram positive pathogens

  • MRSA and VRE

• Does not cause toxicity

When does antibiotic resistance occur?

• When an organism develops a mechanism to elude the activity of an antimicrobial drug that it should otherwise be susceptible to

  • Gene for antibiotic resistance can either be encoded on a plasmid or directly within the genome

• Resistance is prevalent because of widespread and sometimes incorrect use of antibiotics

  • Medicine, veterinary medicine, agriculture

How do we prevent antibiotic resistance?

• Infection prevention

• Rapid and conclusive diagnosis

• Appropriate/ prudent use of antibiotics

• Prevention of transmission

What’s a mechanism that penicillin does?

• Reduced permeability

What’s an example for inactivation of antibiotic?

• Penicillins, chloramphenicol, aminoglycosides

What’s an example for alternation of target?

• Erythromycin, streptomycin, norfloxacin

What’s does sulfonamides do?

• Development of resistant biochemical pathway

What antibiotics work for efflux?

• Tetracyclines, chloramphenicol, fluoroquinolones