Antimicrobial Drug resistance

What drives the development of antimicrobial drug resistance?

Selective pressures from drug exposure, adaptation via genetic change (mutation, gene transfer). Resistant microbes outcompete sensitive ones.

What percentage of hospital-acquired bacterial infections are drug-resistant (CDC)?

~70% show resistance to at least one antibacterial drug.

What evidence supports the role of selective pressure in resistance?

Higher drug use = more resistance

Longer treatment = higher colonization by resistant microbes

Resistant strain patients receive more antibiotics

Resistance prevalence tracks with drug usage patterns in facilities

What are the four general molecular mechanisms of antimicrobial resistance?

Drug inactivation (e.g., enzymes)

Target modification (e.g., mutated binding sites)

Reduced permeability (drug can't enter)

Efflux pumps (active drug removal)

How do microbes resist β-lactam antibiotics (e.g., penicillins)?

Produce β-lactamase (inactivates drug) - often plasmid-encoded

Modify PBPs (drug can't bind target)

Reduce drug permeability

Pump the drug out (efflux)

How do bacteria resist chloramphenicol?

Produce chloramphenicol acetyltransferase (inactivates drug)

Decrease membrane permeability to drug

How do microbes become resistant to sulfonamides?

Alter dihydropteroate synthetase (binding site of PABA analog)

Mutant enzyme avoids drug but still binds normal substrate

hat genetic events contribute to resistance evolution?

Random mutations (polymerase errors)

Recombination

Horizontal gene transfer (Conjugation, Transduction, Transformation, Transposition)

intrinsic resistance

Natural, pre-existing resistance due to cell structure/metabolism (e.g., Gram-negative PBPs in periplasm, fungal efflux pumps).

How do resistance genes arise in nature without human drug use?

Microbes compete by producing natural antibiotics,others evolve resistance (microbial warfare).

Resistance is often a side-effect of normal microbial function (e.g., efflux systems).

What two routes lead to new resistance gene acquisition?

Mutation of existing genes

Acquisition of new genes via mobile genetic elements

Why does resistance often arise only 4-5 years after a drug's release?

High mutation rates

Horizontal gene transfer

Short generation times

Recombination + plasmid mobility

How does agriculture contribute to drug resistance?

40-80% of antibiotics used in farmed animals

Used for growth promotion & disease prevention

May contribute to resistance in human pathogens (data inconclusive)

Why is changing agricultural antibiotic use difficult?

Varies by country

Economic dependence on increased animal size/health

Policy enforcement challenges

What are current strategies to fight antimicrobial resistance?

Reduce use

Use narrow-spectrum or selective drugs

Use drug cocktails

Improve infection control

Develop vaccines

Improve access to new drugs

Develop next-gen antimicrobial compounds

What are lasso peptides, and why are they promising new antibiotics?

Structurally knotted peptides with dual action (Bind 16S rRNA, Bind A-site tRNA)

Cause mistranslation and block protein translocation

Effective against A. baumannii

Low cytotoxicity

Insensitive to known resistance mechanisms

Lariocidin (LAR)

A lasso peptide from Paenibacillus sp. with broad-spectrum activity, shown to disrupt translation and resist common resistance pathways.