Examples: Mycobacrterium Tb and Pseudomonas aeruinosa are naturally resistant to large # of antibiotics = limitation of treatment options

Intrinsic (natural) resistance: innate ability of bactra to resist a particular antibiotic b/c of its structure or characteristic○

Can be spontaneous/random (e.g. M. Tb) or may occur due to exposure to an antibiotic during therapy

One example of this was from the transposable elements in the bacterium that insert near the resistance gene to upregulate it

Mutational Resistance: antibiotic resistance due to chromosomal mutation○

Acquired Resistance: Antibiotic resistance from horizontal gene transfer (swapping genetic material b/w neighboring bactra)○

Cite difference b/w intrinsic, mutational, and acquired resistance-

Learning Objectives

Transformation: involves uptake of short fragments of naked DNA (this doesn’t happen that often though, since nucleases break  it down when it is captured by the bactra)

Transduction: involves transfer of DNA from one bactra into another via bacteriophages

Hence this kind of transfer won't work if the bactra is dead□

Conjugation: transfer of plasmid via sex pilus (F plasmid); reqs cell-to-cell contact

In acquired resistance, there are 3 forms of horizontal gene transfer ○

Cite differences b/w transformation, transduction, and conjugation w/ respect to how bactra acquire extrachromosomal DNA-

Resistance to β-lactam antibiotics (like penicillin) primarily occurs through the production of β-lactamases (enzymes that inactivate β-lactam antibiotics by breaking the β-lactam ring)

Think of this drug as destroying the "garage floor" of the β-lactam house

β-lactamases are encodewd either by chromosomal genes or by transferable genes on plasmids & transposons

β-lactamase genes also frequently resie on integrons (which carry multiple resistance genes)

β-lactamases (aka penicillinases)□

Enzymatic inactivation

For hydrophilic molecules to pass through the membrane of bactra, they have to go into the membrane Porin channels□

Larger the antibiotics, the more hydrophilic it is = less likely it will penetrate through the outer membrane□

Some mutations will cause a loss of specific porins that β-lactams usually entered through□

Decrease permeability

Efflux (spit it back out)

Some of the antibiotics that act on ribosomal binding sites (tetracyclines, macrolides, lincosamides, aminoglycosides) may no longer work if these sites arealtered

Alteration of ribosomal target site□

Vancomycin & other glycopeptide antibiotics bind to d-ala d-ala, which are found in peptidogylcan precursors. If this is altered, the antibiotics won't work 

Alteration of cell wall precursor target site□

β-lactam antibiotics kill bactra by pinding to Penicillin Binding Proteins (PBP) = prevent peptidoglycan from forming

MRSA (methicillin resistant S. aureus) is by the expression of mecA gene, which encodes PBP2a (protein w/ low affinity for β-lactam antibiotics)

Alteration of Target Enzyme□

Alteration of target site

Protection of target site

Overproduction of target

Bypass inhibited process (altered metabolic pathway)

7 distinct mechs of antibiotic resistance; many organisms exhibit a combo of multiple mechs of resistance to a given antibiot ic○

Cite major mechs by which bactra can be resistant to antibiotics-

β-lactamases are classified according to their amino acid structure (A to D)○

PRIMARILY found in KLEBSIELLA, E.COLI, and PROTEUS (PiKE; like the frat)□

ESBLs are enzymes that are resistant to extended spectrum (3rd gen) cephalosporins (ceftazidime, cefotaxime, and ceftriaxone)and monobactams (aztreonam)□

Usually use carbapenems

However, they do not affect cephamycins (type of β-lactam that looks similar to cephalosporin) or the carbapenems (the tanks)□

Extended-Spectrumβ-lactamases (ESBL)

AmpC β-lactamases are chromosomal enzymes that confer resistance to penicillins, narrow-spec cephalosporins, and cephamycins□

 Not susceptible to β-lactamase inhibitors (those combo drugs)□

Observed in Enterobacteriaceae other than Klebsielle and E.coli□

Amp C β-lactamases

Carbapenemases confer the largest antibiotic resistance spectrum□

They can hydrolyze carbapenems + broad-spec penicillins, cephalosporins, and cephamycins□

Carbapenemases

β-lactamases are also classified by the types of β-lactam antibiotics it can destroy○

Cite the various classifications of the beta-lactamases-

This semisynthetic class of penicillin is used for penicillin-resistant Staph aureus (other than MRSA) and Staph epidermidis□

However, this is not effective against enterococci or β-lactamase producing Gram- bactra□

Penicillinase-resistant Penicillin

β-lactamase inhibiters bind irreversibly to the enzyme and neutralize the activity of the enzyme = prevents the antibiotic frombeing hydrolyzed□

Clavulanic acid, Sulbactam, and Tazobactam ("STiCk it B!tch)1.

3 types of β-lactamase inhibitors□

β-lactramas inhibitor combo

Extended Spectrum Cephalosporin (3rd and 4th gen) are resistant to many β-lactamases (ESBL and carbapenase producers are resistant to these guys though)

 

You can use β-lactam antibiotics on some bactra that are producing β-lactamase if you use:○

Discuss the action of beta lactamase inhibitors (e.g. clavulanate)-

Condensed NotesSunday, August 24, 2014 10:40 PM

  Microbiology Page 1

 

Carbapenem: Class of β-lactam antibiotic w/ broad-spec antibacterial activity; highly resistant to most β-lactamases, including ESBL

  Microbiology Page 2