Antimicrobial drugs

Treat diseases within host destroying/inhibiting pathogen at low enough concentrations to avoid damage to host, ideally exhibit selective toxicity

Antimicrobial agents

Streptomyces

Streptomycin antibiotics were discovered from

Bacteriostatic synthetic antibiotics

Sulfonamides are a type of

Genus streptomyces

Most of the antibiotics made today are sourced from

Antibiotics

Antimicrobial agents of microbial origin

• inhibition of cell wall synthesis

• Inhibition of cell membrane function

• Inhibition of protein synthesis

• Inhibition of nucleic acid synthesis

Ways in which antimicrobial drugs can act

• inhibit transpeptidation enzymes such as penicillin binding proteins that build peptidoglycan layers in CW

• This causes a incomplete CW and resulting lysis and death

Inhibition of cell wall synthesis

• selective inhibitors of CW synthesis

• Inhibit transpeptidation enzymes then some inactivate inhibitors of autolytic enzymes to cause lysis

• + & - have different susceptibility to these meds

• Low toxicity in mammalian cells

Beta-lactam antibiotics MOA

• pathogens with ability to produce beta-lactamases that inhibit beta-lactam, which can be plasmid or chromosomally mediated

• Extended spectrum beta lactamases made by g- have increased resistance to certain drugs ex. Cefotaxime

  • Ex. Klebisella pneumoniae

Beta-lactam drug resistance

• Ex. clavulanic acid

• High affinity to beta-lactamase enzymes, bind to them and inhibit to cause BL resistant pathogens to become sensitive

  • amoxicillin/clavulanate (augmentin)

Beta-lactamase inhibitors

Inhib cell membrane function

Disrupt membrane and permeability properties

Polymyxins

Inhib cell membrane

Interfere with biosynthetic functions and teichoic acid synthesis

Nalidixic acid and novobiocin

Inhib cell membrane

Rapid diffusion of cations through membrane

Inophores / valinomycin

Inhib cell membrane

Bind to cell causing depolarization of membrane to increase intracellular potassium to cause death

Daptomycin

Inhib protein synthesis

• bind 30s causing mRNA misreading

• Streptomycin and gentamycin

Aminoglycosides

Inhib protein synthesis

• bind to 50s to inhibit polypeptide chain elongation

• Azithromycin and clarithromycin

Macrolides, azalides, ketolides, lincosamide

Inhib protein synthesis

• bind to 30s to interfere aminoacyl-tRNA binding

Tetracyclines

Inhib protein synthesis

• bind to 50s inhibits peptidyl transferase

• Bacteriostatic

Chloramphenicol

Inhib protein synthesis

• specifically inhib G+

• interferes translation by inhib invitation complex at 23s ribosome

Oxazolidinones

Inhib protein synthesis

• enterococci and mycobacteria infections

Linezolid

Inhib nucleic acid synthesis

• bind to DNA-dependant RNA polymerase to inhib RNA formation

Rifampin

Inhib nucleic acid synthesis

• inhib DNA gyrases/topoisomerase to prevent replication, transcription and repair

Quinolones and fluoroquinolones

Inhib nucleic acid synthesis

Sulfonamides, trimethoprim, pyrimethamine

• down regulation of porin channels, showing carbapenem and polymyxin antibiotic resistance

• Streptococci have natural permeability barrier to Aminoglycosides

Changing permeability for resistance

1. Modification of penicillin binding proteins to lower beta-lactam Ex. Methicillin resistant staphylococcus aureus (MRSA)

2. Erythromycin resistant have altered receptor on 50s

Altered structural target for resistance

• enzymes can still perform functions but are less effected by drug

• EX. In Trimethoprim resistant bacteria dihydrofolic acid reductive is inhib

Altering enzymes for antibiotic resistance

Efflux systems expel antibiotics

• ex. some G- Ex. Pseudomonas aeruginosa up regulate efflux pumps

Develop effluent systems resistance

• enterococcus faecium

• Staphylococcus aureus

• Klebsiella pneumoniae

• Acinetobacter baumannii

• Pseudomonas aeruginosa

• Enterobacter species

The 6 pathogens highly virulent and antibiotic resistant

• G+ resistant to oxacillin and BL

• Commonly found in nose. Or skin

• 2% of people have MRSA form which can cause serious infection and pneumonia

Staphylococcus aureus

• G+ resistant to vancomycin

• Blood, urine, surgical site infections

• Nearly all infections are due to healthcare exposures increased risk at long term hospital stays

Enterococci

• extended spectrum beta lactamase producing G-

• Resistant to penicillin, 1 2 3 gen cephalosporins

ESBL Enterobacteriaceae

• resistant to last resort antibiotics ex. Imipenem (penum’s)

• Produce carbapenemase to inactivate carbapenems

• High mortality

• Colistin/tigecycline can be used to treat by can be toxic

CRE enterobacteriaceae

• very resistant and can contaminate facilities, outbreaks can occur if not controlled

• Resistant to carbapenems

Acinetobacter

• G+, anaerobic, spore forming

• Produces toxins that damage intestine lining and triggered by antibiotics that disrupt gut bacteria

• More than half cases are in long term care

Clostridioides difficile

• fungal pathogen

• Very invasive with high mortality rate

• Highly transmissible

Candida auris