Exam 1: Antimicrobial Resistance Flashcards
What is minimum inhibitory concentration?
The lowest concentration of a drug that will completely inhibit growth of a bacterial strain
When is a bacterial strain resistance to an antibiotic?
When its MIC is higher than the normally achievable and tolerated concentration of the drug attained in tissues with maximum dosage
How do antibiotics act?
By inactivating a specific bacterial target
What are mechanisms of antibiotic resistance?
Modification of the antibiotic target
Enzymatic inactivation of the antibiotic
Impermeability
Active efflux
What do beta-lactams (penicillins and cephalosporins) do?
Alteration of the target protein (penicillin-binding protein) so that the antibiotic no longer binds it
What are penicillin-binding proteins?
Bacterial enzymes that mediate crosslinking of peptidoglycan in formation of the cell wall
What is the modification of the target antibiotic resistance a common mechanism of?
Causing gram-positive bacterial beta-lactam resistance
What is an example of enzymatic inactivation of the antibiotic?
Beta-lactamase
What are beta-lactamases?
Bacterial enzyme that cleaves the beta-lactam ring
Where is beta-lactamase secreted by gram-negative?
Periplasmic space
Where is beta-lactamase secreted by gram-positive?
Into extracellular fluid
What are beta-lactamases usually active against?
A subset of beta-lactam antibodies
What can beta-lactamase inhibitors (clavulanic acid) do?
Prevent inactivation by beta-lactamases
What does the gram-negative outer membrane do in impermeability?
Limits antibiotic access to the cytoplasmic membrane because antibiotics must first diffuse through pores in outer membrane
What is impermeability thought to be the reason for?
E. coli innate resistance to macrolides
What do mutations in porins do to impermeability?
Limit diffusion of antibiotics
A single porin mutation can confer resistance to more than one antibiotic type
What is an example of active efflux?
Tetracycline
What is tetracycline?
Bacterial cytoplasmic membrane proteins that catalyze energy-dependent transport of tetracycline out of the cytoplasm
What does active efflux do?
Prevents sufficient antibiotic concentrations in the cytoplasm to inhibit protein synthesis
What does the active efflux system also exist for?
Quinolones
How does antibiotic resistance arise?
Genetic mechanisms
Phenotypic variants
Biofilms
What are the genetic mechanisms of antibiotic resistance?
Genetic resistance is likely to be detected by susceptibility testing; therefore, it is usually detected at the onset of therapy
Unlikely to appear during a course of antibiotic therapy
What are the 2 mechanisms that genetic resistance can arise?
Gaining the ability to resist one or more antibiotics by acquisition of genes
Resistance from random mutations
What are antibiotic resistance genes usually acquired on?
Plasmids
What do almost all antibacterial drugs have?
A corresponding resistance gene on at least one type of R plasmid
What do resistance (R) plasmids do?
Mediate resistance to more than one antibiotic
What can plasmids carry?
Transposons
What does gene acquisition typically result in?
Rapid acquisition of high-level resistance
What enzymatic antibiotic inactivation and active efflux require for the function to acquired?
The acquisition of a gene
What can the altered antibiotic target strategy occur by?
Acquisition of a gene encoding an altered target
What type of mutation are the random mutations typically?
Point mutations (change of one base pair into another)
What can random mutations do?
Revert back to the original gene sequence
What can a single base pair change result in?
High level resistance, but often multiple mutations have to be acquired so development of resistance can be gradual
How can random mutations result in resistance?
By either reducing permeability or altering target affinity
What can random mutations do in addition to causing antibiotic resistance?
They can be deleterious and cause some degree of growth impairment, and in some cases cause reduction in virulence (fitness cost)
What is fitness cost?
Often the mutation causing resistance also has a cost due to decreased function of the altered target
What do random mutations carry more than horizontal gene transfer?
Fitness cost
What mechanisms of antibiotic resistance does gene acquisition act by?
Alteration of target
Inactivation of antibiotic
Active efflux
What mechanisms of antibiotic resistance does random mutation act by?
Alteration of target
Impermeability
Why can phenotypic variants not be detected on antibiotic sensitivity testing?
It is not genetic
What are the types of phenotypic variants?
Bacterial persisters
Small colony variants
L-forms
What are bacterial persisters?
Non- or slow-growing reversible phenotypic variants of the wild type, tolerant to bactericidal antibiotics
What is persister tolerance of antibiotics due to?
Inhibition of essential cell functions during antibiotic stress, resulting in inactivity of the antibiotic target
What does persistence require?
Coordinated metabolic changes
What is entry and exit from the persister state regulated by?
Signal molecules
What do small colony variants have?
Reduced electron transport, which leads to decreased ATP syntheesis
What is the cause of reduced electron transport in small colony variants?
Reduced hemin or menadione biosynthesis or defective thymine deficiency
What is the result of reduced electron transport in small colony variants?
Decreased metabolism and decreased uptake of antibiotic, causing temporary antibiotic resistance
When do L-forms occur?
When bacteria lose their cell wall
They are temporarily more resistance to beta-lactam antibiotics
Where are L-forms found?
Historically in gram-negative, but recently found in listeria and mycobacterium
When do L-forms work?
When bacteria are in an environment where they are not susceptible to osmotic lysis
What is biofilm?
A structure community of bacteria enclosed in a self-produced polymeric matrix and adherent to an inert or living surface
What can bacteria in a biofilm do?
Convert into a regular planktonic state
What is resistance due to in biofilm?
Slower growth rates of bacteria within biofilms
Decreased diffusion of antibiotics through the biofilm
Accumulation of enzymes that contribute to resistance
Activation of stress response in bacteria in biofilms
Where can biofilms be found?
Indwelling catheters
