Antibiotics and Resistance: How Treatments Work and Why Resistance Emerges

1) What antibiotics target (and how that maps to bacterial structures)

Antibiotics work because bacteria have cellular parts and biochemical steps that are either absent in humans or sufficiently different that they can be targeted selectively. Instead of memorizing drug names, focus on the logic: an antibiotic interferes with a process the bacterium must do to grow or survive, and the effect depends on whether the drug is bactericidal (kills) or bacteriostatic (halts growth so the immune system can clear).

A. Cell wall synthesis (building and cross-linking)

Many bacteria rely on a rigid cell wall to prevent osmotic rupture. Antibiotics that block wall synthesis weaken the wall so the cell can lyse, especially during active growth when new wall is being built.

• Core idea: stop the enzymes that assemble or cross-link wall components → wall becomes fragile → cell bursts or cannot divide properly.
• When they work best: rapidly dividing bacteria (more wall-building activity).
• Practical implication: if symptoms improve slowly, it may be because the drug is stopping growth (static) rather than rapidly killing, or because bacteria are in a low-growth state (e.g., within a biofilm).

B. Protein synthesis (ribosomes as targets)

Bacteria make proteins using ribosomes that differ from human ribosomes. Antibiotics can bind bacterial ribosomes and disrupt translation, which prevents production of enzymes, structural proteins, and virulence factors.

• Core idea: block initiation, elongation, or accuracy of translation → proteins are not made correctly or not made at all.
• Typical outcomes: growth arrest (often bacteriostatic), though some protein synthesis inhibitors can be bactericidal in certain contexts.
• Practical implication: because protein synthesis is continuous, these drugs can reduce toxin production even before bacteria are fully cleared.

C. DNA/RNA processes (replication and transcription)

Bacteria must replicate DNA and transcribe RNA to divide and respond to the environment. Antibiotics can interfere with enzymes involved in DNA supercoiling, replication, or RNA synthesis.

• Core idea: disrupt DNA copying or RNA production → the cell cannot divide or maintain essential gene expression.
• Typical outcomes: often bactericidal because DNA damage or replication failure is catastrophic.
• Practical implication: these drugs may be especially effective in infections with high bacterial burden, but resistance can emerge quickly if exposure is suboptimal.

D. Metabolic pathways (key bacterial chemistry)

Some antibiotics block bacterial metabolic steps that humans do not perform in the same way (or at all). A classic logic is targeting synthesis of essential building blocks (e.g., nucleotides) by blocking pathway enzymes.

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• Core idea: block a pathway bacteria need to make essential molecules → growth stops.
• Typical outcomes: often bacteriostatic unless combined with another blocker in the same pathway (a “sequential blockade” can become bactericidal).
• Practical implication: dietary intake in humans does not “rescue” bacteria if the targeted pathway is internal and required for rapid growth in the host environment.

2) Why antibiotics do not treat viral infections

Antibiotics target bacterial-specific structures and enzymes. Viruses are fundamentally different: they do not build a bacterial cell wall, do not have bacterial ribosomes, and do not carry out independent metabolism. Instead, viruses use host cell machinery for most steps of replication.

• No cell wall to block: viruses are not surrounded by a peptidoglycan wall that must be synthesized during division.
• No bacterial ribosomes: viruses rely on the host’s ribosomes to translate viral proteins, so a drug that targets bacterial ribosomes has nothing to bind in a virus.
• No independent metabolic pathways: viruses do not run the metabolic networks that many antibiotics disrupt.
• Replication is host-dependent: even when viruses encode their own polymerases, the overall replication strategy is not the same as bacterial DNA replication and cell division.

Practical takeaway: giving antibiotics for a viral illness does not shorten the viral course, but it can still cause harm by selecting for resistant bacteria in the patient’s microbiota and by causing side effects.

3) Resistance mechanisms (how bacteria survive antibiotic exposure)

Resistance means bacteria can grow despite antibiotic levels that would normally inhibit or kill them. Mechanisms fall into a few repeating patterns. A useful way to think is: the drug must reach its target, bind its target, and retain activity. Resistance interferes with one or more of these steps.

A. Enzymatic degradation or inactivation

Bacteria can produce enzymes that destroy the antibiotic or chemically modify it so it no longer works.

• Logic: antibiotic enters → enzyme breaks/changes it → drug cannot bind target.
• Clinical clue: resistance can be high-level and sudden once the enzyme gene is acquired.

B. Target modification (change what the drug binds)

If the antibiotic’s binding site changes shape, the drug binds poorly or not at all.

• Logic: drug arrives intact → target is altered → binding fails → bacterial process continues.
• How it happens: mutation in the target gene or acquisition of an alternative target protein.
• Practical implication: this can cause cross-resistance within a class of antibiotics that share the same binding site.

C. Efflux pumps (push the drug out)

Efflux pumps are membrane proteins that export antibiotics from the cell faster than they accumulate.

• Logic: drug enters → pump removes it → intracellular concentration stays below effective level.
• Practical implication: efflux can create low-to-moderate resistance across multiple unrelated drugs (multidrug resistance) if the pump is broad-spectrum.

D. Reduced permeability (keep the drug from getting in)

Some bacteria reduce antibiotic entry by changing membrane channels or surface properties.

• Logic: fewer entry points or altered membrane → less drug reaches the inside → target is protected.
• Practical implication: reduced permeability often combines with other mechanisms (e.g., efflux), producing stronger resistance than either alone.

E. Biofilm-associated tolerance (surviving without classic resistance)

Biofilms are structured communities attached to surfaces (e.g., catheters, teeth, chronic wounds). Cells in biofilms can be harder to eradicate even if they are not genetically “resistant.” This is often called tolerance rather than resistance.

• Physical barrier: the biofilm matrix can slow antibiotic penetration.
• Slow growth states: many antibiotics work best on actively dividing cells; dormant or slow-growing cells survive.
• Persister cells: a small subpopulation can temporarily withstand antibiotics and regrow later.

Key distinction: resistance is usually inherited (genetic), while tolerance can be a reversible physiological state. Clinically, both can lead to treatment failure.

4) How resistance spreads: selection pressure, mutation, and horizontal gene transfer

A. Selection pressure (why exposure matters)

In any large bacterial population, there may already be rare variants that survive better under antibiotic stress. Antibiotics remove susceptible bacteria and leave survivors to multiply.

• Step-by-step logic:
  1. A mixed bacterial population exists (mostly susceptible, a few more tolerant/resistant).
  2. Antibiotic exposure kills/inhibits susceptible cells.
  3. Survivors face less competition and expand.
  4. The next infection (or relapse) is more likely to be resistant.
• Where selection happens: at the infection site and also in the normal microbiota (gut, skin), which can become a reservoir of resistance genes.

B. Mutation (new resistance arising during replication)

Mutations occur naturally during DNA replication. Most are neutral or harmful, but occasionally a mutation reduces drug binding or changes drug handling.

• Step-by-step:
  1. Bacteria replicate rapidly.
  2. Random mutations occur.
  3. Under antibiotic pressure, mutants with survival advantage persist.
  4. Those mutants become the dominant strain.
• Practical implication: incomplete or suboptimal exposure (wrong drug, wrong dose, too short, poor absorption) can increase the chance that partially inhibited bacteria survive long enough for resistant mutants to expand.

C. Horizontal gene transfer (sharing resistance genes)

Bacteria can acquire resistance genes from other bacteria, sometimes even across species. This can spread resistance faster than mutation alone.

• Conjugation: direct transfer of DNA (often plasmids) through cell-to-cell contact.
• Transformation: uptake of free DNA from the environment.
• Transduction: DNA transfer mediated by bacteriophages.

Practical implication: environments with frequent antibiotic exposure (healthcare settings, long-term care, repeated courses) can amplify gene exchange by favoring bacteria that carry mobile resistance elements.

5) Stewardship concepts (principles-level)

Antibiotic stewardship means using antibiotics in a way that maximizes patient benefit while minimizing resistance and harm. The goal is not “use fewer antibiotics” in isolation; it is “use the right antibiotic strategy when antibiotics are truly needed.”

A. Appropriate use (only when bacterial infection is likely)

• Match treatment to syndrome: some symptom patterns are more consistent with viral illness (self-limited, prominent upper-respiratory symptoms, diffuse aches) while others suggest bacterial disease (localized findings, certain types of pneumonia, urinary symptoms with supportive testing).
• Consider severity and risk: in high-risk patients, clinicians may treat empirically while awaiting tests; in low-risk patients, watchful waiting may be safer.

B. Adherence and correct exposure (dose, timing, duration)

Resistance risk increases when bacteria are exposed to antibiotic levels that are too low or too inconsistent to clear the infection.

• Step-by-step for patients (general principles):
  1. Take doses at the prescribed intervals to keep effective drug levels.
  2. Do not save leftover antibiotics for future illness.
  3. Do not share antibiotics with others.
  4. If side effects occur, contact a clinician rather than stopping abruptly without guidance.

C. Infection prevention (reduce the need for antibiotics)

• Vaccination: prevents infections that might otherwise lead to antibiotic use (including secondary bacterial complications).
• Hand hygiene and environmental cleaning: reduces transmission of resistant organisms.
• Device management: minimizing unnecessary catheters/lines reduces biofilm-associated infections that are hard to treat.

D. Diagnostics (treat the cause, not just the symptoms)

Diagnostics help distinguish bacterial from viral illness and identify which antibiotic is likely to work.

• Principle: obtain appropriate samples when feasible (before antibiotics in many settings) to increase the chance of identifying the pathogen.
• Use results to narrow therapy: once a bacterial cause and susceptibility pattern are known, choose the most targeted effective option rather than broad coverage.

Case-based discussion: bacterial vs viral, and resistance risk factors

Use the following cases to practice two decisions: (1) Is the illness more consistent with bacterial or viral cause? (2) If bacterial treatment is considered, what resistance risk factors might be present?

Case 1: Sore throat and congestion

Scenario: A 19-year-old has 3 days of sore throat, runny nose, cough, hoarse voice, and low-grade fever. Several friends have similar symptoms. No shortness of breath. Symptoms are improving slightly today.

• Decision A (likely cause): Which features point toward viral vs bacterial?
• Decision B (antibiotics?): Would an antibiotic target a plausible bacterial process here, or is supportive care more consistent with the biology?
• Resistance risk check: Even if antibiotics were given “just in case,” what selection pressure would that create in the person’s normal microbiota?

Case 2: Urinary symptoms with prior antibiotic exposure

Scenario: A 45-year-old has burning urination and urinary frequency for 2 days. No cough or runny nose. They took antibiotics for a dental infection 6 weeks ago. They have had two similar urinary infections in the past year.

• Decision A (likely cause): Which symptoms suggest a bacterial process localized to the urinary tract?
• Decision B (diagnostics): What test(s) would help confirm bacterial infection and guide targeted therapy?
• Resistance risk factors: recent antibiotic use, recurrent infections (possible repeated selection), and potential prior resistant strains.

Case 3: Pneumonia-like symptoms after influenza

Scenario: A 67-year-old had a flu-like illness that improved after 5 days, then developed new high fever, worsening cough, and shortness of breath. They have diabetes and were hospitalized last year.

• Decision A (likely cause): How does “improved then worsened” change your suspicion for secondary bacterial infection?
• Decision B (resistance risk): Which factors increase the chance of resistant bacteria (recent hospitalization, comorbidities, possible healthcare exposure)?
• Mechanism link: If a resistant bacterium is present, which resistance strategies (e.g., reduced permeability + efflux, enzymatic inactivation) could plausibly undermine therapy?

Case 4: Skin wound with slow response

Scenario: A 30-year-old has a painful, red skin lesion with drainage. They started an antibiotic 48 hours ago with minimal improvement. They report frequent gym use and a prior similar lesion. The lesion is near an area of friction from clothing.

• Decision A (bacterial vs viral): Does the localized, purulent lesion fit viral replication patterns or bacterial tissue infection more closely?
• Decision B (why not improving?): List at least three possibilities: wrong diagnosis, inadequate drainage/source control, resistant organism, poor penetration into a collection, or biofilm/tolerance in a chronic lesion.
• Step-by-step next actions (principles):
  1. Reassess severity and need for urgent care.
  2. Consider whether source control is needed (e.g., drainage) in addition to antibiotics.
  3. Obtain a sample for culture when appropriate to identify the organism and susceptibility.
  4. Review adherence and dosing schedule.
  5. Re-evaluate risk factors for resistant organisms based on exposures and prior antibiotic use.