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• Metabolic antagonists


  Substances that interfere with metabolic processes
• Synthesis of nucleotides


  1. Tetrahydrofolate (THF) is essential for many of these

  2. Humans absorb folate from diet

  3. Bacteria must synthesize THF
• Metabolic antagonists


  • Sulphonamides
  • Trimethoprim
• Trimethoprim-sulfamethoxazole


  Synergistic action on 2 steps towards tetrahydrofolate production
• Trimethoprim


  Inhibits dihydrofolate
• Sulfamethoxazole


  Inhibits PABA
• Metabolic antagonists


  • Often considered bactericidal
  • Toxic (skin reactions, bone marrow) so used to treat or prevent serious infections such as Pneumocystis pneumonia, Nocardia infections
• Dihydropteridine phosphate


  Synergistic Drug Interactions
• Resistance to sulphonamides/sulfa drugs


  • Alteration of target enzymes
  • Changes in permeability
  • Hyperproduction of PABA may overcome blockade
• DNA Replication


  • Requires many different enzymes
  • DNA polymerase replicates bacterial chromosome
  • Topoisomerases regulate supercoiling of DNA strands
• Quinolones


  • Broad-spectrum, synthetic drugs containing the dual 4-quinolone rings
  • Act by inhibiting topoisomerases DNA gyrase and Topoisomerase IV
• Quinolones


  • Nalidixic acid (originator)
  • Ciprofloxacin
  • Moxifloxacin
• Resistance to quinolones


  • Mutations in topoisomerase-encoding genes
  • Porin-poor outer membrane
  • Efflux pumps
• Metronidazole


  • Nitro group on core ring must be reduced for activity
  • Only achieved by anaerobes
  • Free radicals generated damage to DNA & Cell death
• Potential pitfalls of β-lactams


  • Some organisms do not use peptidoglycan
  • Penetration into infected cells (ineffective against intracellular pathogens)
  • Porins in G-ve bacteria needed to gain access to PBPs, "Porin-poor" strains exist
  • Efflux pumps transport antibiotics back out of the cell (most effective for G-ve as they can pump out of the outer membrane)
  • Low affinity binding (may be acquired or intrinsic - vary between organisms anyway)
  • Penicillinases (β-lactamases) enzymes that degrade β-lactam ring
• Transmission of Resistance


  • Chromosomal genes passed on during cell division to "all" progeny
  • Mobile genetic elements (plasmids, transposons, integrons) genes on these can move within and / or be freely exchanged between bacteria
  • Gene cassettes "sets" of related or unrelated resistance genes can exist as separate genetic elements or can be part of transposon, integron or chromosome
• Gram-positive organisms of clinical importance
• Gram-positive cocci


  • Staphylococci
  • Streptococci
  • Enterococci
  • Peptococci/Peptostreptococci
• Gram-positive rods


  • Clostridia
  • Corynebacteria (diphtheroids)
  • Listeria
  • Bacillus
• Two most common groups of Gram-positive organisms of medical importance


  • Staphylococci
  • Streptococci
• Staphylococcus aureus


  Gram stain
• Staphylococci


  • Bunch of grapes appearance
  • Catalase-positive
  • Hardy, ubiquitous in nature, many are normally harmless commensals
  • Infections can be relatively trivial or rapidly fatal
  • Often resistant to natural penicillins (Pen G/V)
• Staphylococcus aureus


  • Golden colonies
  • Most virulent Staphylococcus
  • Coagulase producer: fibrinogen to fibrin
  • Frequently carried by healthy people, even MRSA often found on/in patients and healthcare staff
• Virulence factors of Staphylococcus aureus

  • Protein A (binds to IgG, exerts anti-phagocytic effect)
  • Fibronectin-binding protein/FnBP (promotes binding to mucosal cells and tissue matrices)
  • Cytolytic exotoxins (haemotoxins, attack mammalian cell membranes)
  • Superantigen exotoxins (stimulate enhanced T cell response, toxic shock syndrome)
• Coagulase-negative staphylococci (CNS/CoNS)


  • Staphylococcus not aureus
  • Lower virulence than S. aureus
  • Acquired drug resistance (β-lactams) is more common than in S. aureus
  • Vancomycin-sensitive
• Staphylococcus saprophyticus


  • Part of the normal flora of female genital tract / perineum
  • Causes cystitis (infection of the bladder) especially in younger women
• Overview of Staphylococci


  • Overview of Staphylococcus aureus (virulence factors, infections, treatment)
  • Overview of coagulase-negative staphylococci (CNS)
  • Overview of Staphylococcus saprophyticus
• Streptococci


  Twisted chains appearance
• Types of haemolysis on blood agar

  • Gamma: no haemolysis
  • Beta: complete lysis of red blood cells
  • Alpha: partial lysis, discoloured
• Streptococcal classification schemes


  • Haemolytic properties
  • Serologic grouping (Lancefield)
• Group A β-haemolytic Streptococci (GAS)

  • Streptococcus pyogenes
  • Nasopharyngeal carriage, spread via respiratory droplets and skin contact
• Major virulence features of Group A β-haemolytic Streptococci

  • Capsule (hyaluronic acid)
  • Cell wall fixed proteins
  • Extracellular products (exotoxins)
• Streptococcus agalactiae (Group B β-haemolytic Streptococci)


  • Normal flora of GI tract, vaginal tract, urethra
  • Leading cause of meningitis and septicaemia in neonates - High mortality rate
• Streptococcus pneumoniae (Pneumococcus)


  • α-haemolytic, diplococcus
  • Nasopharyngeal carriage, extremely sensitive to environment
  • Commonest bacterial cause of community-acquired lower respiratory tract infection
• Streptococcus pneumoniae


  • Capsule is the most important virulence factor, composed of polysaccharide, antiphagocytic and antigenic
• Clinical significance of Streptococcus pneumoniae


  • Pneumonia
  • Otitis media
  • Bacteraemia/sepsis
  • Meningitis
• Streptococcus pneumoniae treatment


  • Always sensitive to penicillin until 1980s, resistance is increasing due to PBP changes
  • High doses may overcome raised MIC, except for meningitis
  • Vancomycin or moxifloxacin
• Gastrointestinal gram-negative rods


  • Diverse taxonomy, only a fraction of the total organisms within the GI tract
  • Can cause diseases in the GI tract, within the body or both
  • Faecal contamination is the route of transmission (faecal-oral)
• Escherichia coli (E. coli)


  • Normal flora in colon of humans and other animals
  • Pathogenic within and outside GI tract
  • Fimbriae/pili adhere to mucosal surfaces
  • Motile or non-motile
  • Ferment lactose (Lac+)
• Structural antigens of E. coli

  • O
  • H
  • K