Eukaryotic Cells

Beginnings of Antimicrobial Drug Therapy

• Paul Ehrlich, a chemist, created arsenic compounds that could kill microbes. His "magic bullets" targeted the bacteria Treponema pallidum, which causes syphilis, and the protozoa Trypanosoma, which causes African sleeping sickness.
• Alexander Fleming discovered that the antibiotic penicillin is released from the mold Penicillium.
• Gerhard Domagk discovered sulfanilamide, the first widely available antibiotic and a metabolic inhibitor.
• Selman Waksman found that microorganisms like Streptomyces bacteria yield useful antimicrobials, and he coined the term antibiotics for drugs derived from living organisms that kill or inhibit bacteria.
• Antibiotics are antimicrobial agents produced naturally by organisms.
• Semi-synthetics are chemically altered antibiotics that are more effective than naturally occurring ones.
• Synthetics are antimicrobials completely synthesized in a lab.

Spectrum of Activity of Antimicrobial Drugs

• Antimicrobial drugs act against a number of different pathogens.
• Narrow-spectrum drugs are effective against few organisms.
• Broad-spectrum drugs are effective against many organisms.
• Broad-spectrum drugs may allow for superinfections to develop and kill normal flora, reducing microbial antagonism.

Antimicrobial Drugs: Agents

• Cidal agents are chemicals that kill microbes, including bactericidal, fungicidal, virucidal, and protozoaicidal substances.
• Static agents are chemicals that inhibit or control growth, such as bacteriostatic, fungistatic, virustatic, and protozoastatic substances.
• Static Agents that inhibit or control the growth of microbes, depend on the immune system to eliminate organisms

Determining Efficacy of Antimicrobial Drugs

• The Kirby-Bauer susceptibility test involves placing disks with different antibiotics on a bacterial lawn. Clear zones around disks indicate growth inhibition.
• Tube-dilution method determines the, minimum inhibitory concentration (MIC) and the minimun bactericidal concentration (MBC).
• Bacteriostatic agents prevent growth.
• Bactericidal agents kill microbes.

Determination if Antibiotic is Clinically Useful

• An antibiotic's MIC may stop growth in the lab, but not in a patient.
• Drug concentration in tissue must remain higher than the, MIC. Some patients take doses once or three times a day to maintain this concentration.

Chemotherapeutic Index

• The chemotherapeutic index is the ratio of the toxic dose of an antibiotic to its therapeutic dose.
• Selective toxicity, harming the pathogen and not the host, is key.
• Therapeutic dose is the minimum dose per kilogram of body weight needed to stop pathogen growth. T-oxic dose is the maximum dose tolerated by the patient.
• A higher chemotherapeutic index results in a safer drug.

Bacterial Targets of Antibiotics

• Antibiotics can target metabolic inhibitors, DNA replication, RNA polymerase, protein synthesis, cell membrane, and cell walls.

Antibiotics that Inhibit Cell Wall Synthesis

• Cell wall inhibitors include penicillins, cephalosporins, vancomycin, bacitracin, and monobactams.
• Most common agents prevent the chain elongation and cross-linkage of NAM subunits.
• These agents prevent bacteria from increasing the amount of peptidoglycan.
• These agents are effective only for growing cells and have no effect on existing peptidoglycan layers.

Beta-Lactam Antibiotics

• Beta-lactam antibiotics act on beta-lactam rings similar to the D-alanine-D-alanine part of peptidoglycan.
• Beta-lactams bind to enzymes called penicillin-binding proteins (PBPs) that cross-Nam link subunits. Inhibition of PBPs lead to cell lysis from cell structure irregularities
• Rroups all are involved in final synthesis synthesis of peptidoglycan.

Beta-Lactams Inhibit Synthesis of Bacterial Cell Walls

• Normal cell walls are made, New subunits are inserted enzymes.
• Subunites Old/New nam, cross Links are formed to Peptide cross-links.

Semi-synthetic derivatives

• are derivatives of Penicillin and Cephalosproin
• They are more stable in acidic environments, more readily absorbed and active against most bacterias.
• some penicillin forms are ampicillin and amoxicillin.
• Some Cephalosporin forms Cefotaxime Ceftriaxone Ceftaroline

Other Antibiotics that Target Peptidoglycan Cell Wall Synthesis

• Cycloserine inhibits enzymes that make the peptide side chain on NAM. It's used to treat tuberculosis.
• Bacitracin blocks NAG and NAM secretion from the cytoplasm out to the cell wall. In combination with polymyxin, bacitracin is used topically agains gram positives. Kidney damage is a side effect.
• Vancomycin targets the peptidoglycan precursor molecules by binding the peptide end of the new NAM-NAG disaccharide and it's used against penicillin resistant bacteria. Interferes to subunits linking NAM Side effects include kidney damage and impaired hearing. Used agains Gram positive bacteria.

Antibiotics that Target Mycolic Acid Synthesis

• Isoniazid (INH) disrupts mycolic acid formation in mycobacterial species and has a narrow spectrum.
• Because of its limited effectiveness, INH is used in combination with other antibiotics like ethambutol, streptomycin, and rifampin for 6–9 months.

Resistance to Cell Wall Inhibiting Antibiotics

• Bacteria can gain resistance to penicillin by inheriting a gene encoding beta-lactamase enzymes.
• Beta lactamase cleaves beta-lactam rings in Penicillin.
• Mutations may alter penicillin-binding proteins that synthesize the cell wall but don't bind with penicillin when they develop resistance to Penicillin.

Antibiotics that cause Cell Membrane Damage

• Polymyixins create Cation that disrupt polaridy disrupting channel which desrupt cells and all cell procesesses.
• Gramicidin a peptide bonds a charge that disrupt Inner memebranse and phospholipids. Gram is given to Bacitracin Kidney failure due to long run topical.

Antibiotics that Target Mycolic Acid Synthesis

Lipid carriers are destroyed for use of acid and formation. Isoniazid INHDs is disruption if mycobacterial speties. Treating 6/8 Month with ethambutol riffing.

Antibiotics that affect DNA Synthesis and Integrity

Metronizadole (Flagly) Select Toxic since people lack the abicty to produce free adiclas when reduce cell. Anaerobic or aerobic.

ANTIBIOTICS - SULFA DNA

Drugs, or folic acid, inteferees DNA syntheisis with folic acid.

What don't sulfa affect on mammals

• Mammals dont syntheiss for it

Antibotics That effect metabolism/ DNA Synthesis

Analogs bind reversibity to produce folic aicd. trimetroprime- effects the nuecleic acids by blocking step two to making THF

Antibiotics that Inhibit DMA Replication

Quiliones do this.

• broad, g+ an g- bacteria
• flovin ad animia are added to the bacteria

Why not Quinomes affect human cells?

Human cells are different strutully

Antibiotics that Inhibit RNA Synthesis

RifAMPN

Antibiotics that Inhibit Protein Synthesis

Interfeers with subunit and robsomes Target bacterial 70s v 30s S

Antibiotics that Affect on Ribosomes 30s

Change the share mRNA is read Translocation Advantment P site Styptomycin geny tetra binds with calicum not to young kids

Ribsomes 50s

Aminos to prevents peptidy

• narrow range, and dearecs red bioid Marcuides binds in diffrenet movement from sites. Ertmyocin allgeres

LINCO

peptidyl prevents bonds foramtion

• effective CLY

streptogranings;

diffrent sites a subunt act syncertislty. Ex syercidy last restiond

Mechanisms of Antibiotic Resistance

• Modify target/ binding
• Add modity alter
• Efflux pomps
• pass metabolicpathway Biofirms

Development of Antiobitc restisnce

• mutations, and conjugation livestocs

Antibitoic Patherns

• Staph auertus enterici

Multi-Drug resistance

• Pathogens accutre to three or mr drug

Cross Drug resistencge

• Drug and organin

- Antibitoic Admeirserbtaion

Infection theated Bacterial edidgy ex

Lighting Drug restorance

Dutnt tagrts

• structrue
• combinng

Anti oral Agents

Virus cel funion, toxicity

Anti ral Agents

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Vaccantion

ANTI I VENTS

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Anti ral DNA & RNA Synthesis

Drugs are rensible Select Toix bc they do not make cell

Acyclovirs

Blcok synthesis Virus & hepes

Selectively thoxic

RIBA blcok SYNTESIS INfluenza C hepc

SARS - CoV2 Agents

covid transmistion symptoms prevation

PALLVOID agents

treatmet inhibit

Anti oral DRugs

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H I V lntergrates

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HIV Proteaes/Hhibtors NEV

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h I V

Prorease inhibtors is a therapy

Anti Fungi Agent

Fungal infection difficullt to trat SImillar to us Detoxify

REpeated and dertoxifs and Mic is needed long

ANTI FUNGI AGEBNTS

• polyneres Azoles Allys Gries Echeno

Ny

Pore

. Anti Fungi membrane distruotps

Used topcial candla Amphercin is aggressive Bonds the membranes and desroys. stertol on membranse Inhibits Ergosterol Nitraet inftction of ski candida moist sk topical

Fungu

- inhibits ergestergol

itazol

• used treament fulgy inhibits estol

• Terbsn fungi topical

• block cell diveion

• intravinous

synthieis osmatic ###. Anti Prozoal Agents

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