Bacterial Genetics And Antibiotic Resistance

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ways bacteria resist antibiotics

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degrade or alter antibiotic(split beta lactam ring, modify aminoglycosides)
efflux pump (tetracyclines, macrolides)
uptake reduced (cephalosporins)
overproduction of target metabolic bypass (sulfonamides, trimethoprim)
alteration of target (PBP-transpeptidases, 50S ribosomal subunit modified and macrolide cant bind, DNA gyrase/topoisomerase interferes with fluoroquinolones)

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pathogens develop resistance through natural selection

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when bacteria are exposed to antibiotic, more susceptible organisms will be killed and resistant bacteria will continue to grow

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Antibiotic misuse

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given when they arent needed
more than 70% of all antibiotics are used in animal feedstock to promote faster growth
continued when they arent needed
given at the wrong dose
wrong antibiotic chosen
some countries allow antibiotics to be purchased over the counter

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genetics of antibacterial resistance

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vertical gene transfer- genetic change from parent to offspring through mutation
horizontal gene transfer- from one bacteria to another, through transformation, transduction and conjugation

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mutations

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any change in the base sequence of a cells DNA
spontaneous mutations- repair systems make mistakes every so often
induced mutation- mutagens cause them (chemical, physical)
if mutation provides selective advantage the mutant population will quickly dominate

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mutations continued

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may arise prior to or in the absence of selective pressure- random events
most antibiotic resistance occurs by point mutations (insertion, deletion, substitution)

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horizontal gene transfer

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transformation- transfer of naked DNA from a donor cell to a recipient
transduction- transfer of genetic material from one bacteria to another by a bacteriophage (virus)
conjugation- transfer of DNA between bacterial cells by direct contact via sex pilus

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genetic recombination

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new genetic material must be integrated into the chromosome/plasmid of the host
homologous- occurs between closely related DNA sequences and generally substitutes one sequence for another
nonhomologous- occurs between dissimilar DNA sequences and generally produces insertions or deletions

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transformation

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transfer by means of naked DNA
donor cells lyse and release DNA, DNA attaches to a host cell where it is cut into pieces by nucleases and reduced to a single strand, remaining strand integrates into the host DNA by looking for a region of sequence homology, invading strand replaces one of the host strands and undergoes replication
Insignificant effect on bacterial resistance

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bacteriophage

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virus that replicates inside a bacterial cell, phage nucleic acid takes over biosynthetic machinery to replicate its own and synthesizing phage-specific proteins

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virulent phage and temperate phage

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virulent phage- multiplication of the phage within the cell results in lysis and release of phage particles
temperate- after entering the cell the phage integrates into specific sites within the host chromosome-called a prophage (state of lysogeny)
expression of the phage genes are repressed and the phage DNA replicates as part of the host chromosome, after induction the phage undergoes the normal lytic cycle

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transduction

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transfer of genes from one bacteria to another by a phage
generalized transduction- transfers any bacterial gene
specialized transduction- transfers only genes adjacent to site of integration of lysogenized temperate phage

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generalized transduction

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a random piece of bacterial DNA is accidentally encapsulated in a phage protein coat
when this particle infects a new host cell it injects the bacterial DNA fragment into the cell
new DNA can become integrated into the host chromosome by recombination

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specialized transduction

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after induction, genes located next to the prophage may be excised and replicated along with the phage DNA
when the phage infects another cell, both chromosome and phage DNA integrates into the new recipient

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conjugation

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unidirectional transfer of genes from one cell to another by contact
certain plasmids (F) can transfer themselves
donor cell makes a sex pilus that makes contact with receptor sites on recipient cell
pilus retracts into donor cell bringing donor and recipient into close contact (no DNA passes through the sex pilus)
occasionally the F plasmid integrates itself into the bacterial chromosome
when the plasmid is transferred to another cell it drags along the chromosome with it
integration of the recipient cell occurs by homologous recombination via a double crossover

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conjugative resistance (R) plasmids

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found in many gram neg. bacteria
contains the F factor (replication and transfer genes)
contains resistant genes often coding for multiple resistance

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structure of R plasmid

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RTF (resistance transfer factor) carries the replication and transfer genes (F)
R determinant- contains multiple transposons with resistance genes
resistance genes are often parts of transposons (jumping genes)

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transposons (mobile genetic elements)

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can move form place to place on the chromosome and into and out of plasmid
carry both insertion sequences plus other genes often those coding for resistance
if transposon inserts into a functional gene it will be destroyed resulting in cell death
considered to be a biological mutagen

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rapid development of antibiotic resistance

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overuse of antibiotics
R plasmids
transposons/integrons
spontaneous mutations
other means of horizontal gene transfer

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integrons

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often in transposons
they can capture multiple gene clusters called gene cassettes and integrate these into the genome
allows a number of different resistance genes to be transferred as a unit from one bacteria to another

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solutions to the problem

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reduce antibiotic usage
develop new classes of antibiotics and vaccines
contain resistance in the hospital
build alliances to decrease access to antimicrobials
fund more research