Antibiotics, Antivirals and Infections

• Antimicrobial is a broad group that includes antivirals, while antibiotics specifically target bacterial growth through death or inhibition.
• Less than 1% of discovered antibiotics have commercial value due to bacterial change over time, making specific antibiotics less useful.
• Broad-range antibiotics and narrow-range antibiotics exist, but antibiotic resistance and toxicity are major concerns.
• Antibiotic discovery receives significant research funding, but many potential antibiotics are toxic to humans and cannot be used.

Infection Types

• Hospital-acquired infections manifest after 48 hours of hospitalization, whereas community-acquired infections are contracted outside the hospital.
• Community-acquired infections show symptoms within 48 hours of hospitalization, indicating the patient brought the infection with them.

Discovery of Antibiotics

• Antibiotics originate from natural sources like fungi and bacteria or can be designed synthetically (de novo).
• Fungi and bacteria produce antibiotics for competitive reasons.
• Penicillium mold produces penicillin to compete with other organisms.
• Bacteria that produce antibiotics are not susceptible to them due to their resistance mechanisms, which give them a competitive advantage.
• Synthetic antibiotics are useful because the bacteria may take longer to develop resistance than natural compounds, which have natural analogs.
• Computer modeling programs can design small molecules to fit and bind tightly into the active sites.

Rational Design

• Rational design involves thinking about the drug development process before the drugs are even marketed for human use.
• Rational design offers a structured approach to target specific components in bacterial cells and assess potential impacts on human cells.
• Selecting a protein crucial for bacterial cell wall synthesis minimizes the likelihood of affecting human cells.
• Rational design enables the use of higher antibiotic concentrations due to increased specificity and reduced toxicity.

Classification

• Broad-spectrum antibiotics target a wide range of bacterial infections.
• Narrow-spectrum antibiotics target particular species.
• Broad-spectrum antibiotics target both gram-positive and gram-negative bacteria.
• Penicillin is an example of a narrow-spectrum antibiotic, typically targeting gram-positive bacteria.
• Broad-spectrum antibiotics may be used in emergencies when the causative bacteria are unknown or multiple bacteria are suspected.

Structural Classes

• Cyclic lipopeptides are a class of drugs derived from design in a lab.
• The source for Cyclic lipopeptides is strep throat.
• Cyclic lipopeptides target gram-positive bacteria, including multi-drug resistant strains.

Bacteriostatic vs Bactericidal

• Bacteriostatic drugs slow down cell activity by inhibiting DNA or protein synthesis, eventually leading to cell death.
• Bactericidal drugs outright kill bacteria, often by disrupting the cell wall.
• Erythromycin is an example of a bacteriostatic drug that interferes with protein synthesis.
• Penicillin is an example of a bactericidal drug because it disrupts cell walls.

Minimum Inhibitory Concentration & Minimum Bactericidal Concentration

• Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are assessed before clinical trials.
• Drug companies determine the mechanism of action and whether the antibiotic is bactericidal or bacteriostatic.
• The minimum concentrations required to inhibit (MIC) or kill (MBC) bacteria are determined in vitro.
• Antibiotics are tested with cell cultures and animal models before testing on humans.

Inhibition of Cell Wall Synthesis

• Beta-lactams block peptidoglycan synthesis, an essential component of bacterial cell walls.
• Beta-lactams directly interact with enzymes required for peptidoglycan synthesis.
• Beta-lactams are more effective against gram-positive bacteria due to their mechanism of action.
• Beta-lactams are bactericidal because they cause significant damage to cell walls.
• A resistance mechanism against drugs that use beta lactams is antibiotic degradation.
• Beta-lactamase is an enzyme that breaks down the beta-lactam ring, rendering the antibiotic non-functional.
• Cell wall breakdown results in spheroplasts, which are vulnerable to osmotic pressure.

Disruption of Plasma Membrane

• Polymyxins disrupt the inner and outer cell membranes.
• Daptomycin targets gram-positive bacteria, while polymyxin targets gram-negative bacteria.
• Polymyxins are broad-spectrum and acts by inhibiting protein synthesis.

Aminoglycosides

• Aminoglycosides are procured.
• Aminoglycosides cause misreading of the tRNA codon.
• Aminoglycosides target gram-negative aerobic and facultative anaerobic bacteria.

Methotrexate (MTX)

• MTX is used to treat psoriasis and as an anticancer drug.
• MTX inhibits DNA synthesis, affecting both human and bacterial biology.
• Cancer patients taking MTX are susceptible to bacterial infections.
• MTX can stimulate antibiotic resistance in bacteria.

Tetracycline

• Tetracycline inhibits the initiation of translation.
• Tetracycline targets both gram-positive and gram-negative bacteria.

Macrolides

• Macrolides prevent protein allocation and interfere with ribosomes and binding.
• Macrolides target gram-positive and gram-negative bacteria.

Sulfonamides

• Sulfonamides inhibit folate synthesis, which is essential for DNA production
• Sulfonamides are broad-spectrum antibiotics.
• Sulfa allergies are common and should be checked for.
• Sulfonamides are bacteriostatic because they inhibit DNA synthesis.

Multi-Drug Treatments

• Multi-drug treatments use a cocktail of different drugs to treat infections
• Multi-drug treatments are used in the treatment of TB.
• Multi-drug treatments are required due to the development of antibiotic resistance.
• Isoniazid inhibits mycolic acid synthesis, a component of mycobacteria cell walls and is bactericidal.
• Ethambutol is bacteriostatic.
• Multi-drug treatments for TB usually last four months or longer and can cause discomfort
• Patients may stop taking the drugs when they feel better, which can lead to antibiotic resistance in the remaining bacteria.
• If the patient stops taking the cocktail, it will not be as effective if they become sick again.

General Complications of Antibiotic Use

• Multi-drug treatments are crucial due to the high resistance of Mycobacterium tuberculosis to multiple antibiotics.
• Administering a combination of at least four different antibiotics increases the likelihood of clearing the bacteria from the patient's system.
• Nurses may need to administer the drug to ensure that the patient takes it every day.

Evolutionary Mechanisms

• Antibiotic resistance occurs when bacteria evolve and change over time.
• Random mutations can make efflux pumps more effective.
• Bacteria can undergo adaptation of receptor.
• Plasmids of pathogenicity can cause the bacteria to resist antibiotics.
• Bacteria can develop enzymes that degrade antibiotics.

Bacterial Cell Division

• Bacteria divide rapidly, leading to frequent mutations.
• Bacterial populations select for adaptation to their environment.
• Resistance can be acquired through genetic mutation.

Receptor Adaptation

• An example of resistance is MRSA (methicillin-resistant Staphylococcus aureus).
• Antibiotics should not be overused in medicine to prevent the development of resistance.
• Doctors may sometimes avoid prescribing antibiotics for viral infections due to patient's resistance.
• Antibiotics have been overused in long-term care facilities and agriculture.
• In agriculture, antibiotics make make animals grow faster via muscle gain,.
• Antibiotic-free options are now available.

Plasmids

• Plasmids are extra, smaller, circular DNAs in bacterial cells containing genes for degrading antibiotics, which bacteria can transfer to other cells via conjugation.
• Conjugation occurs when two cells meet; one cell knows it doesn't contain a plasmid, and the cell that does contain the plasmid builds a protein bridge between the cells.
• In conjugation, the plasmid is transferred as a single strand into the recipient cell, then becomes double-stranded, so both cells now have the plasmid.
• Plasmids often contain antibiotic resistance genes.
• Plasmids are helpful and important for the hospital environments.

Transformation

• Transformation is when bacteria acquire DNA or genes from another bacteria.
• Bacteria that is free in the environment can pick up free chunks of DNA and incorporate it into their own genome.
• Bacteria can import long pieces of DNA through pores for incorporation.
• The incorporated DNA may contain antibiotic resistance genes.

Three Mechanisms of Antibiotic Resistance

• Random mutation
• Conjugation
• Transformation