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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 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 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 o 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”