L5. Staph A Antibiotic Resistance Flashcards
How soon did penicillin resistance appear after its introduction?
Clinical resistance for penicillin appeared a few years after its introduction.
What is the mechanism behind penicillin resistance?
Penicillin resistance is mediated by β-lactamase, an enzyme that bacteria use against each other.
What are semi-synthetic β-lactams and give an example?
Semi-synthetic β-lactams are chemically modified antibiotics derived from β-lactam structures; an example is Methicillin.
How long did it take for resistance to Methicillin (Semi-synthetic B-lactam) to appear?
Resistance to Methicillin appeared within a few years of its use in Staphylococcus aureus (MRSA).
Why was Vancomycin considered a last resort antibiotic?
> Vancomycin was thought to be resistant-proof because resistance would require a massive change in the bacterial cell wall.
> But it was very toxic
What is the state of antibiotic resistance as of 2024?
By 2024, penicillin is considered useless, semi-synthetic β-lactams can still be used, and Vancomycin resistance is spreading.
What is MRSA and why is it a major issue?
MRSA stands for Methicillin-resistant Staphylococcus aureus, and it is a major issue because it is resistant to all β-lactams.
What antibiotics are MRSA resistant to?
MRSA is resistant to penicillins, cephalosporins, carbapenems, penems, and all β-lactam derivatives.
What other resistances does MRSA have?
MRSA has the capacity to be resistant to other antibiotics such as erythromycin, tetracycline, streptomycin, and even disinfectants.
Why is it problematic to administer many antibiotics?
Many antibiotics can have significant side effects and are not pleasant for patients to take.
How do β-lactams kill Staphylococcus aureus?
β-lactams bind to penicillin-binding proteins (PBPs) involved in the final stage of peptidoglycan production where substrate precursors are transglycosylase and transpeptidase work to cross link, which is essential for maintaining cell viability under pressure.
Why are β-lactams effective at killing Staphylococcus aureus?
Peptidoglycan synthesis occurs outside the cell membrane, making PBPs accessible targets for β-lactams for gram positive bacteria (not for gram negative due to outer membrane).
What is PBP2a and its significance in methicillin resistance?
PBP2a, encoded by the mecA gene, has a low affinity for β-lactams, allowing Staphylococcus aureus to resist these antibiotics.
How does PBP2a function despite the presence of β-lactams?
PBP2a works by having a low affinity for β-lactams due to an altered binding site, allowing peptidoglycan cross-linking to continue.
Where did the mecA gene come from, and how did it contribute to resistance?
The mecA gene likely originated from an exogenous source, such as Staphylococcus sciuri, and was acquired by horizontal transfer.
What happens during the horizontal transfer of mecA in Staphylococcus aureus?
Staphylococcus aureus acquires a 30-50kb mec element flanked by insertion sequences, facilitating the transfer and integration of the mecA gene.
What is the benefit of mecA only being expressed in the presence of antibiotics?
As mecA is from a foreign bacteria, it has not evolved to work with Staph A machinery so continuous expression of mecA could be harmful to the bacterium, so it is regulated to be expressed only when antibiotics are present.
What are the two regulatory mechanisms controlling mecA expression?
The two regulatory mechanisms are mecI and mecR.
What is the role of mecI in mecA regulation?
mecI is a repressor that binds upstream of mecA and blocks its transcription in the absence of β-lactams.
How does mecR regulate mecA expression in response to β-lactams?
mecR senses β-lactams, undergoes a conformational change, and hydrolyses mecI, relieving its repression on mecA and allowing mecA expression.
What happens to mecI in the presence of β-lactams?
In the presence of β-lactams, mecR hydrolyzes mecI, leading to mecA expression.
Describe the environmental signaling process involving mecR and mecI.
mecR senses β-lactams and activates to hydrolyze mecI, allowing mecA expression only when antibiotics are present.
What happens when no β-lactam is present?
When no β-lactam is present, mecR is inactive, and mecI binds to mecA, repressing its transcription.
What type of protein is mecR and what does it do?
mecR is a metalloprotease activated by β-lactams, which hydrolyzes mecI, leading to mecA transcription.
When were fluoroquinolones introduced and why were they initially effective?
Fluoroquinolones were introduced in the mid-1980s. They were initially effective because they were synthetic and bacteria had not encountered them before, so no existing resistance mechanisms had evolved.
What class of antibiotics does Ciprofloxacin belong to and what is its MIC for MRSA?
Ciprofloxacin belongs to the fluoroquinolones class, with an MIC (Minimum Inhibitory Concentration) of less than 2 µg/ml against MRSA.
What was Ciprofloxacin (type of fluoroquinolone) used for in MRSA treatment?
Ciprofloxacin was used to cure the nasal carrier state of MRSA.
How quickly did MRSA strains develop resistance to Ciprofloxacin (type of fluoroquinolone)?
Resistance in MRSA strains to Ciprofloxacin increased from 5% to 80% within one year.
What causes resistance to Ciprofloxacin (type of fluoroquinolone) in MRSA?
Resistance is due to point mutations in the DNA gyrase target, specifically altered codon 84 or 85, and can spread via horizontal transfer and evolutionary pressure.
What is the current status of mupirocin in treating infections?
Mupirocin is now used, but resistance has appeared, as it does with every antibiotic.
What is the only currently effective drug against MRSA?
Vancomycin, a glycopeptide antibiotic, is currently the only effective drug against MRSA.
How does Vancomycin work and why is it effective against Gram-positive bacteria?
Vancomycin inhibits peptidoglycan biosynthesis by binding to D-Ala D-Ala at the end of peptide building blocks causing steric hinderance (as vancomycin is so large it stops incorporation into peptidoglycan), effective against Gram-positive bacteria because it targets the cell wall outside the membrane.
How does Vancomycin work in both mature and growing cells?
Vancomycin binds to a building block for cell wall growth, target is present in the mature wall too.