week 5

• Antimicrobials


  A natural or synthetic substance that kills or prevents growth of a microorganism
• Antibiotic


  Kills or prevents growth of bacteria
• Antimicrobial Resistance (AMR)


  When microbes (e.g. bacteria and viruses) evolve in such a way they are no longer affected by antimicrobial medicines
• Estimated 10 million deaths per year could be attributed to AMR by 2050
• David Cameron, former UK Prime Minister: 'If we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work, and we are cast back into the dark ages of medicine'
• WHO priority pathogens - Priority 1: CRITICAL

  • Acinetobacter baumannii, carbapenem-resistant
  • Pseudomonas aeruginosa, carbapenem-resistant
  • Enterobacteriaceae, carbapenem-resistant, ESBL-producing
• WHO priority pathogens - Priority 2: High

  • Enterococcus faecium, vancomycin-resistant
  • Staphylococcus aureus, methicillin resistant, vancomycin intermediate and resistant
  • Helicobacter pylori, clarithromycin-resistant
  • Campylobacter spp., fluoroquinolone resistant
  • Salmonellae, fluoroquinolone resistant
  • Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone resistant
• Beta-lactam antibiotics


  A class of broad-spectrum antibiotics, consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems
• Macrolides


  A class of antibiotic that includes erythromycin, roxithromycin, azithromycin and clarithromycin. They are useful in treating respiratory, skin, soft tissue, sexually transmitted, H. pylori and atypical mycobacterial infections
• Tetracycline


  Works by binding specifically to the 30S ribosome of the bacteria, preventing attachment of the aminoacyl tRNA to the RNA-ribosome complex. It simultaneously inhibits other steps of the protein biosynthesis
• Aminoglycosides


  Once inside the bacterial cell, they bind to the 30s ribosomal sub-unit and cause a misreading of the genetic code. This subsequently leads to the interruption of normal bacterial protein synthesis
• Fluoroquinolones


  First mechanism of action - inhibition of DNA gyrase. They act by inhibiting the activity of both the DNA gyrase and the topoisomerase IV enzymes. For most Gram-negative bacteria, DNA gyrase is the primary fluoroquinolone target
• Mechanism of Antibiotic Resistance

  • Restricted Access
  • Enzymatic Manipulation of Drugs
  • Modification of Drug Target
  • Failure to Activate Drug
• Restricted Access - Outer Membrane Porins

  Antibiotics must reach their target molecules in order to have an effect. Gram-negative bacteria express proteins called porins to allow essential molecules to pass through the outer membrane. Antibiotics can take advantage of these porins thereby gaining access through the outer membrane. Mutations in genes encoding porins can change the diameter of the pores, resulting in resistance to larger antibiotics
• Restricted Access - Efflux Pumps


  Efflux pumps are proteins located in the cytoplasmic membrane. Their normal function is to pump small molecules out of the bacterial cytoplasm. Some efflux pumps have high specificity to metals and compounds and therefore play an important role in homeostasis of the cell. However, some are non-specific and pump out a range of antimicrobial agents, resulting in the occurrence of multidrug resistance
• Classes of Efflux Pumps

  • Antiporters
  • ABC transporters
• Gram-negative bacteria can have more complex efflux pump systems with pumps consisting of proteins spanning the cytoplasmic membrane, the periplasm and the outer membrane
• Enzymatic Inactivation of the Antibiotic

  Bacteria can inactivate antibiotics through enzymatic manipulation, such as breaking down the beta-lactam ring in penicillin, modifying aminoglycosides, or acetylating chloramphenicol
• Modification or Protection of the Antibiotic Target

  Bacteria can become resistant by modifying the target molecule that a drug usually binds to, either through accumulation of spontaneous mutations or chemical additions/changes to the targets, such as methylation, which impedes antibiotic binding but still allows normal functionality
• Penicillin Binding Proteins (PBPs)


  Modifications in penicillin binding proteins prevents the binding of Beta-lactam antibiotics, thus preventing their actions. This type of resistance is most common among gram-positive bacteria and is causing current Beta-lactam resistance problems
• Ribosome Protection


  Bacteria can become resistant by modifying the ribosome target that some antibiotics bind to, preventing the antibiotic from binding and inhibiting protein synthesis
• Failure to Activate an Antibiotic

  Many drugs are administered in their inactive form so that they have no or limited effect before they arrive at their target site. Resistance can occur when the normal pathways for activating the drug, such as enzymatic reactions or pH changes, are changed, thus preventing the drug from switching on and carrying out its function
• The pathway to antimicrobial resistance can be very energetically expensive and time consuming for bacteria. Therefore, bacteria share their genes to pass on the developed resistance through Horizontal Gene Transfer
• More than 60% of human infections each year are attributable to zoonotic diseases
• Limited understanding of the natural prevalence and circulation of AMR bacteria in the wild animal population, including avian species. Currently limited national surveillance studies looking at AMR in wildlife
• Essential to monitor potential pathogen reservoirs which may facilitate pathogen spillover events. Presence of AMR bacteria in wildlife may be used as an indicator of anthropogenic activities (sewage, slurry, manufacturing waste)
• A study showed that 21% of swabs from a 10 mile stretch of the River Cam contained potentially dangerous Pseudomonas spp., all of which were resistant to at least one drug and 75% were multi drug resistant
• The study showed that resistance is widespread and not limited to isolated locations, but unable to say where the birds picked up the resistant bacteria or where they may transfer it to