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What is antibiotic resistance and why is it considered a major global health threat?

Antibiotic resistance is the ability of bacteria to survive exposure to antibiotics that would normally kill them or inhibit their growth. It is a major global health threat because it leads to treatment failure, increased mortality, and was estimated to cause 10 million deaths annually by 2050 with huge economic losses.

What were the key predictions of the Review on Antimicrobial Resistance regarding AMR?

The report predicted that by 2050 antimicrobial resistance could cause 10 million deaths per year and cost the global economy up to $100 trillion due to reduced productivity and increased healthcare burden.

What is meant by 'the rise of resistance organisms'?

It refers to the increasing prevalence of bacteria that are resistant to multiple or all available antibiotics, making infections harder or impossible to treat.

What is natural (intrinsic) antibiotic resistance?

Natural resistance occurs when bacteria inherently lack the target of the antibiotic or have structural features such as impermeable membranes that prevent antibiotic entry.

Give two mechanisms by which bacteria show natural resistance.

1. Absence of the antibiotic target 2. Impermeable cell wall or membrane preventing drug entry

What is developed (acquired) antibiotic resistance?

Developed resistance occurs when bacteria gain resistance through mutations or acquisition of resistance genes from other bacteria.

What is partial (intermediate) antibiotic resistance?

Partial resistance is when bacteria are less sensitive to an antibiotic but can still be inhibited by higher doses or combination therapy.

What is complete antibiotic resistance?

Complete resistance occurs when bacteria are entirely unaffected by the antibiotic, even at high doses.

What are the four major mechanisms of developed antibiotic resistance?

1. Enzymatic destruction or modification of the drug 2. Modification of the drug target 3. Changes in metabolic pathways 4. Reduced drug accumulation via efflux or reduced permeability

What is the role of β-lactamase in antibiotic resistance?

β-lactamase enzymes break the β-lactam ring of antibiotics like penicillins, inactivating them.

Where can β-lactamase enzymes be found?

They are found in both Gram-positive and Gram-negative bacteria.

What gene commonly encodes β-lactamase?

The bla gene.

What structural component of β-lactam antibiotics is targeted by β-lactamase?

The cyclic β-lactam ring.

What are Extended-Spectrum β-Lactamases (ESBLs)?

ESBLs are enzymes that can hydrolyse a wide range of β-lactam antibiotics, including newer cephalosporins.

What are carbapenemases and why are they clinically important?

Carbapenemases are enzymes that degrade carbapenems, which are last-resort antibiotics, making infections extremely difficult to treat.

What is New Delhi Metallo-beta-lactamase-1?

NDM-1 is a carbapenemase enzyme that confers resistance to nearly all β-lactam antibiotics.

What are aminoglycoside-modifying enzymes (AMEs)?

Enzymes that chemically modify aminoglycoside antibiotics, rendering them inactive.

What are the three main classes of AMEs?

1. Acetyltransferases (AAC) 2. Nucleotidyltransferases (ANT) 3. Phosphotransferases (APH)

Where are AME genes typically located?

On plasmids and transposons.

How do bacteria develop resistance to aminoglycosides via target modification?

By altering the 30S ribosomal subunit, reducing antibiotic binding.

How is resistance to macrolides like erythromycin achieved?

By altering the binding site on the 50S ribosomal subunit.

How do fluoroquinolones resistance occur at the molecular level?

Through point mutations in DNA gyrase (gyrA gene).

What is Methicillin-resistant Staphylococcus aureus?

A bacterial strain resistant to methicillin and other β-lactam antibiotics.

What protein is responsible for methicillin resistance in MRSA?

Penicillin-binding protein 2a (PBP2a).

How does PBP2a confer resistance?

It has low affinity for β-lactam antibiotics, allowing cell wall synthesis to continue.

How do bacteria resist sulfonamides?

By producing a modified dihydropteroate synthase with low drug affinity but normal substrate affinity.

How do bacteria resist trimethoprim?

By synthesising a modified dihydrofolate reductase enzyme with low affinity for the drug.

What is an efflux pump?

A transport protein that actively expels antibiotics out of the bacterial cell.

Which antibiotics are commonly affected by efflux pumps?

Tetracyclines, erythromycin, and fluoroquinolones.

How does altered permeability contribute to resistance?

By reducing antibiotic entry into the bacterial cell, especially in Gram-negative bacteria.

What is chromosomal mutation in antibiotic resistance?

A genetic change in bacterial DNA that alters proteins or pathways targeted by antibiotics.

What can cause chromosomal mutations leading to resistance?

Exposure to antibiotics in the environment.

What is plasmid-mediated resistance?

Resistance genes carried on plasmids that can be transferred between bacteria.

What is a transposon?

A mobile genetic element that can move between DNA locations and carry resistance genes.

What is an integron?

A genetic structure that captures and expresses multiple resistance genes.

What is horizontal gene transfer?

Transfer of genetic material between bacteria via plasmids, transposons, or gene cassettes.

What are the three main mechanisms of horizontal gene transfer?

1. Conjugation 2. Transformation 3. Transduction

Why is plasmid-mediated resistance particularly dangerous?

Because it allows rapid spread of resistance across different bacterial species.

Why are carbapenem-resistant bacteria considered 'superbugs'?

Because carbapenems are last-line antibiotics, so resistance leaves very limited treatment options.

Explain why combination therapy can overcome partial resistance but not complete resistance.

Partial resistance can be bypassed by increasing drug pressure or using synergistic drugs, whereas complete resistance involves mechanisms that fully inactivate or bypass the drug.