Antimicrobials and resistance
Diperkenalkan| English | Makna |
|---|---|
| selective toxicity | selective toxicity |
| penicillin-binding proteins | penicillin-binding proteins |
| horizontal gene transfer | horizontal gene transfer |
| β-lactamase | β-lactamase |
A poison that spares you
- Penicillin can flood your blood and kill bacteria without harming a single one of your own cells.
- Every antibacterial drug exploits a difference between bacterial and human cells, and every resistance mechanism is the bacterium closing that difference.
Selective toxicity
- Selective toxicity 选择性毒性 means hitting a target that bacteria have and human cells lack or build differently.
- There are four main target groups: the wall, the ribosome, DNA enzymes and folate synthesis.
The wall
- β-lactam drugs, such as penicillins, bind the penicillin-binding proteins 青霉素结合蛋白 that cross-link peptidoglycan. The wall weakens and the bacterium bursts.
- Human cells have no peptidoglycan wall, so they are untouched.
Why do β-lactam drugs spare human cells?
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Penicillin-binding proteins build the bacterial wall; human cells have nothing equivalent.
Ribosome, DNA and folate
- Bacterial ribosomes (30S + 50S subunits) differ from ours (40S + 60S), so drugs such as macrolides and aminoglycosides can block them. Quinolones block DNA gyrase.
- Bacteria must make their own folate; we get it from food. Sulfonamides and trimethoprim block that synthesis.
Match each drug group to its target.
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Each target exists in bacteria but not, or not in the same form, in us.
Resistant mutants already exist
- Resistance mutations arise at about $10^{-7}$–$10^{-9}$ per cell per generation. An overnight culture holds about $10^9$ cells per mL, so resistant mutants are present before the first dose.
- Two drugs together need two independent mutations, about $10^{-14}$–$10^{-18}$: that is why tuberculosis is treated with combinations.
A culture holds 10⁹ cells, and resistance arises in 1 cell in 10⁷. How many resistant cells are expected?
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10⁹ × 10⁻⁷ = 10² = 100.
Genes that jump between bacteria
- Horizontal gene transfer 水平基因转移 moves resistance genes on plasmids and transposons, even between species.
- So one success can spread through many kinds of bacteria much faster than new mutations arise.
Resistance genes can pass only from a parent cell to its daughter cells.
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Plasmids and transposons move them between bacteria, even between species.
Four ways to resist
- Destroy the drug: a β-lactamase β内酰胺酶 opens the β-lactam ring. Change the target: MRSA makes PBP2a, which β-lactams cannot bind.
- Pump the drug out (efflux pumps), or keep it out by losing porins in the Gram-negative outer membrane.
How is MRSA resistant to flucloxacillin?
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A changed target defeats the whole β-lactam group, not just penicillin.
Worked example: reading two lines of a report
- (Fictional) S. aureus from an abscess: "β-lactamase positive; flucloxacillin sensitive". Its enzyme destroys penicillin, but flucloxacillin is built to resist that enzyme.
- A true MRSA has a changed target, PBP2a, so flucloxacillin fails as well. Different mechanisms, different drugs.
An S. aureus is β-lactamase positive but flucloxacillin sensitive. Why does flucloxacillin still work?
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The enzyme opens penicillin's ring but not flucloxacillin's; only a changed target (MRSA) defeats it.
Worked example: why one drug fails in tuberculosis
- (Fictional figures) A lung cavity holds $10^{10}$ bacilli. Isoniazid resistance arises in about 1 in $10^6$ cells, rifampicin resistance in about 1 in $10^8$.
- Expected isoniazid-resistant cells: $10^{10} \times 10^{-6} = 10^4$, which one drug alone would select. Resistant to both: $10^{10} \times 10^{-14} = 10^{-4}$, effectively none.
A patient has 10¹⁰ tuberculosis bacilli, and isoniazid resistance arises in 1 cell in 10⁶. How many isoniazid-resistant cells are expected?
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10¹⁰ × 10⁻⁶ = 10⁴ = 10 000, which is why isoniazid is never given alone.
Three common slips
- "Resistance is all or nothing." Susceptibility is measured on a scale and reported in categories.
- "A new drug ends resistance." The same mutation arithmetic restarts with every new drug.
- "Antibiotics do all the work." The immune system does most of the clearing.
Recap
- Targets: the wall (PBPs), ribosome (30S/50S), DNA gyrase and folate synthesis, all bacteria-specific.
- Resistant mutants arise at $10^{-7}$–$10^{-9}$ per cell; combinations multiply the odds; plasmids spread wins.
- Mechanisms: destroy the drug, change the target, pump it out, keep it out.