Download csim2.9: antibiotic resistance 22/01/09

CSIM2.9: ANTIBIOTIC RESISTANCE
22/01/09
LEARNING OUTCOMES
Explain the principles of the development of microbial antibiotic resistance and its transmission
OVERVIEW OF ANTIBIOTIC RESISTANCE
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Antibiotic resistance is becoming an increasing problem in the treatment of many infectious diseases
o This is partly due to increasing use and misuse of antibiotics in therapeutics
o Bacteria that develop resistance to antibiotics can rapidly confer it to other bacteria
o Resistance may therefore be inherent to the bacterium or acquired from other bacteria
o Antibiotics should be administered such that all target bacteria are killed to avoid resistance
There are four key ways in which bacteria can resist against the actions of antibiotics:
o Anti-antibiotic enzyme production e.g. β-lactamase
o Target modification e.g. alteration of receptor sites
o Target shielding e.g. pumps that efflux antibiotics from cells, cell envelope modifications
o Metabolic bypass of metabolism-inhibiting drugs e.g. mass production of intermediates
Acquired antibiotic resistance may be either intrinsic or extrinsic:
o Intrinsic acquisition results from spontaneous genetic mutation – relatively rare
o Extrinsic acquisition results from a genetic exchange between bacteria
GENETIC EXCHANGE
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All bacteria possess a single chromosome but some have an additional separate pool of DNA
o Chromosome – single-stranded circular DNA coil; present in the cytoplasm of all bacteria
o Plasmid – extra-chromosomal loop of DNA that may confer virulence or resistance factors
Genetic material may be exchanged within bacterial populations either vertically or horizontally
o Vertical gene transfer is achieved through binary fission and is intergenerational
 Intrinsically acquired antibiotic resistance spreads through this mechanism
o Horizontal gene transfer can occur in a number of ways and is intragenerational
 Extrinsically acquired antibiotic resistance spreads through this mechanism
Horizontal gene transfer can take place through three unique processes:
o Transformation – importation and incorporation of extra-cellular (free) DNA
 Requires a competent cell – one with the ability to take up free DNA
 Normally involves DNA released from a dead bacterium
 Plasmid DNA is taken up directly; a single strand of chromosomal DNA is extracted
 Competence-specific proteins protect imported DNA from degradation
o Transduction – effectively forced DNA insertion resulting from bacteriophage attack
 Bacteriophages are viruses that specifically infect bacteria
 They contain coiled genetic material in a protein coat that is pumped into bacteria
 In generalised transduction random host chromosomal fragments are packaged into
newly formed bacteriophage heads which then self-assemble and cause cell lysis
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In specialised transduction a lysogenic bacteriophage integrates its DNA into the
host cell chromosome as a prophage which then later causes production of new
bacteriophages containing specific portions of the host cell DNA
Conjugation – involving plasmid transfer via cell-to-cell contact, either direct or via a sex pilus
 The presence of a plasmid confers a “male” gender to bacteria (sex factor)
 Plasmids are commonly found in gram-negative bacilli – diverse genotypes
 The plasmid is copied into the “female” bacterium which then becomes “male”