Treatment and Prevention

Chemotherapy - treatment of disease with a chemical compound dircted against invading mcrobes or abnormal cells

Antimicrobial - agent which kill or inhibit growth of suseceptible organism:

• antibiotics - microbial product which kills or inhibits susceptible organisms. Administer outside the body
• disinfectant - apply to non living or surfaces 
• antiseptic - splly to living tissue

Characteristics of antimicrobial drugs

a, selective toxicity - agent must kill the or inhibit the microbes while damaging the host as little as possible: therapeutic dose and toxic dose

b, range of effectiveness - narrow or broad spectrum

c, pharmacokinetic and pharmacodynamic properties:

• location of infection
• absorption into various body compartment
• route of antibiotic administeration
• dose
• frequency and duration of treatment

d, killing Vs. inhibiting:

• bacteriocidal compounds - antimicrobes which kill the bacteria
• bacteriostatic compounds - antimicrobes that inhibit or reduce the rate of microbial growth

Susceptibility to antibiotics 

Method: gar diffusion method

Minimum inhibitory concentration (MIC) - is the lowest dosage that can be administered that will inhibit the growth of bacteria. 

Mechanisms of antibiotics action 

Prerequisite - unique characteristics of the microorganisms that is different from the host:

• inhibiting cell wall synthesis
• contain DNA gyrase, RNA elongation and they don't undergo translation
• folic acid metabolisms 

Antibiotic resistance 

Intrinsic resistac, natural - occur naturall in all strains. It is chromosomally encoded

Extrinisic resistance, acquired - results of a mutation of the DNA or acquisition of new DNA 

Spread of antimicrobial resistance

Niche competition - result of natural selection

The problem arises under these conditions:

• overuse of antibiotics
• incomplete or incorrect use of therapy
• failure on hospital infection control
• antibiotics as growth enhancer
• global dissemination of resistance strains increases the chnace of spreading 

Mechanisms :

• efflux pump
• reduces uptake
• metabolic bypass
• antibiotic degadation enzyme
• antiobiotic alteration enzyme 
• biofilm

In S. aureus...MRSA 

The hospital strain quickly develop resistance o vairiety of antibiotics. 

β-lactam antibiotics are structualy analogues of D-alanyl-D-adenine dipeptides. They are the temineral AA on precursor disaccharide NAM/NAG subunit of the PH layer. NAM and NAG is cross-linked by transpeptidases in a transpeptidation reaction. β-lactams irreversibly bind to PBP active site → inhibit the transpeptidation reaction. 

Resistance to β-lactam antibiotics:

• production of β-lactamase 
• Penicillin binding protein - onto a large mobile Staaphylococcal chromosomal cassette mec and other several different types. 

Treatment with Vancomycin 

It binds to two types of D-adenyl-D-adenine residues of the PG: 1, periplasmic-located residue 2, cytoplasmic membrane anchor monomers called lipid II.

Bindind to lipid II inhibits the transglycosylation reaction - bactericidial.

Resistance to Vanomycin 

Acquired by mechanisms:

1, thickening of the cell wall

• non-specific substate thta traps vanomycin in the cell wall
• protect the lipid II at the cell membrane 
• multiple gene and pathway alterations

2, synthesis of D-alanyl-D-lactate peptidoglycan precusor 

• low affinity for vancomycin
• modified lipid II 

Drug discovery 

Combinatorial chemistry - analogue of existing antimicrobial compounds.  Rational drug design - production of synthetic inhibitory chemicals Traditional methods - serach for a novel natural compounds from environment  Anti-infectives 

• issolation of anti-bacterials that target virulence determinants 
• specific for pathogenic bacteria
• least likey to evolve a resistace mechanisms 

Urinary Tract Infection

Caused by Uropathgenic E.coli. A recurrent infections is common and it is increasingly ressiatance to antibiotics. 

Screen: biofilm inhibitor 

• formation of biofilm o PVC plate, 24h @ 37c
• stain with crystal violet
• screen for inhibit biofilm 

Vaccines 

• a strategies used to reduce the risk of illness while retaining the ability to induce beneficial immune response
• a biological preparation to improve immunity against a particular disease
• stimulates body to recognise infectious agent
• develop memory - faster recognition and destroy the infectious agent at latter encounters

Screen: biofilm inhibitor 

• formation of biofilm o PVC plate, 24h @ 37c
• stain with crystal violet
• screen for inhibit biofilm 

Vaccines 

• a strategies used to reduce the risk of illness while retaining the ability to induce beneficial immune response
• a biological preparation to improve immunity against a particular disease
• stimulates body to recognise infectious agent
• develop memory - faster recognition and destroy the infectious agent at latter encounters

Types:

• Kill - microorganisms which have been killed or destroyed
• Attenuated - live microorganisms with no virulence properties
• Toxoid - inactiviated compounds
• Subunit - a protein fragment that is immunoreactive
• Conjuagate - combination of polysaccharides linked to immunogenic proteins

Search for new vaccines

1, infection with Tb does not protect against adult TB → new vaccines is needed to confer stronger immune response

2, one third of population is already infected → vaccines that erradiacte the disease

3, co infection with HIV → vaccine must be safe to used in immuno supressed patients 

4, larger percetage of population has been infected with BCG → new vaccine must work in this population

Vaccine development 

Problems: antigenically hypervariable and a need to block bloodstream dissemination of pathogen in asymptomatic carriers. 

A new concenpt of reverse vaccinology made it possible by genome sequencing revolution.