Antibiotics

compound naturally produced by molds and bacteria that inhibits the growth of or kills other microorganisms

1910 - Paul Ehrlich created an arsenic compound to cure syphilis

1928 - Alexander Flemming discovered Penicillum produced penicillin (a toxin) that could kill bacteria but cannot purify it

• chain and Florey purified it 10 yrs later

• succesfully tested in 1941

most antibiotics come from microorganisms that live in the soil

1960s - known drugs could be altered to change efficiency

• Penicilin to ampicillin

A variety of penicillin-like medications exist

other antibiotics have also been altered to give them new characteristics

semisynthetic- natural compounds that are chemically modified

sometimes antibiotics can be synthesized in total in the lab

partially or synthetic chemicals are antibiotics

Antimicrobial Drugs

Selective Toxicity-greater harm to microorganisms than human host

• Interferes with essential structures or properties in Microbes

Antimicrobial Action

Bacteriostatic Drugs - inhibit bacterial growth, hosts defenses eliminate bacteria

Bacterial Drugs - kill bacteria

Drugs can be both Depending on the Situation

Spectrum of Activity

Broad Spectrum - Affect a wide range of bacteria species

• gram pos and neg

  • good for life-threatening infection

    • Disrupts normal flora

Narrow Spectrum - Affects a limited range of bacteria.

• requires less testing the

• bacteria for susceptibility

  • less disruptive

Combing Antimicrobial Drugs - good or bad

synergistic - one drug adds to the activity of another

Antagonistic - one Drug interferes with the other

Additive - no effect

Tissue Distribution, metabolism, and Excretion

where each drug can go varies

Drugs that are destroyed by low pH should not be taken orally

The rate of Drug elimination is expressed as half-life.

• Half-life: time for one-half of the concentration to be eliminated from the body

Adverse Effects

Allergic reactions

Toxic effects

suppression of the normal microbiota - normal flora usually exclude pathogens

• Antibiotics can suppress normal flora causing a new infection

resistance to antimicrobials

Innate/intrinsic - resistance Inherent resistance of bacteria to certain drugs

Acquired resistance - previously sensitive organisms will become resistant through spontaneous mutation of acquisition of new genetic information

Mechanisms faction of Antibacterial Drugs

Take advantage of bacteria processes utilize enzymes or structures different from or absent in eukaryotes

• Bacterial wall synthesis

• protien Syntesis

• Nucleic Acid Synthesis

• Metabolic Patways

• Integrity of Cytoplasmic Membrane

Inhibit Cell Wall Synthesis

B-lactam drugs

• completely inhibit enzymes that perform a critical step in peptidoglycan synthesis.

• enzymes catalyze to formation of peptide bridges between glycan strands

  • peniciln-binding protiens

• Activity varies.

  • some work agast both gram pos. and neg.

• Different types of bacteria have slightly different PBP making some drugs more effective than others

Bacterial Response

• some bacteria synthesize enzymes to destroy penicillin

• Gram-negative bacteria can produce more kinds of B-Ketmases than Gram-positive

Penicillin

Altered in lab, basic structure is the same but side chains are modified

Natural penicillins

• produces mainly by Penicillium mold.

• narrow spectrum

• mostly against Gram pos.

• sensitive to penicillinases

Penicillinase-resistant penicillins

• lab developed to combat penicillinase-producing staff infections

Broad-spectrum penicillin

• modified side chains confer activity against Gram-bacteria and retain activity on gram-positive.

• can still be inactivated by B-lactamases

Extended-spectrum penicillin

• effective against gram res. Pseudomonias specias.

• less effective against gram pos.

• can be destroyed by B-lactamases

Penicilians and Blactmase inhibitor

• chemicals that interfere with some B-lactamase activity

• Administered along with penicillin

Augmentin -Amoxicillin and Clavulanate potassium

other drugs inhibit cell wall synthesis

vancomycin

• blocks synthesis of peptidoglycan run by binding the terminal amino acid of the NAM peptide Side Chain

• Does not cross the outer membrane of negative bacteria

  • innately resistant

Bacitracin

• Interferes with the transport of peptidoglycan can precursors across the cytoplasmic membrane

• very toxic

• mostly used in OTC ointments All things make proteins, but antimicrobial drugs take advantage of differences in bacterial machinery

  • ribosome

Aminoglycosides

• Irreversibly bind 30s subunit bocks initiation and causes misreading ribosomes already translating

• Enters cell throng process that requires respiration

  • not effective against anaerobes

• often used with Blactam drugs that inhibit cell wall synthesis and encourage uptake of the aminoglycoside

• can be toxic

Tetracyclines

• reversibly binds 30s subunit.

• prevents tRNA binding -prevents protien synthesis from proceeding

Macrodides

• Bina reversibly to 50s subunit to prevent proton synthesis

• not effective against Enterobacteria cue because outer membrane excludes drug

chloramphenicol

• Binds 50s subunit and prevents peptide bond formation

• wide range of effectiveness, rare lethal Side effect

• Bacteriostatic

Lincosamides

• Bind 50s Subunit and prevent continuation of protein synthesis

• Wide variety of Gram pos. and rare. bacteria

Oxazolidinones

• Bind with 50s and interfere with protein synthesis initiation

• variety of gram-positive bacteria

Streptogramins

• two used in conjunction and work synergistically.

• Bind two different sides on the 50s subunit and inhibiting different steps of protein synthesis

  • Synercid

  • Individually bacteriostatic

  • together bacteriocidal

  • variety of gram-positive

Inhibit nucleus Acid Synthesis

Fluoroquinolones

• synthetic drugs inhibit on or more topoisomerase

  • maintans superesilery

• wide variety ot gram pos. and neg

Rifamylins

• Block Pmicryotic RNA Polymerase from ititiating transcription

• Gram positive, Gram neg., Mycobacterium

Inhibit Metabolic Pathways

• Inhibit folate pathway-animal cells

• lack pathway

Sulfonamides

• Sulfa drugs

• Gram pos. and Gram neg, bacteria

• structurally similar to PABA

• competitive inhibitors for enzymes in

Trimethoprim

• Inhibits an enzyme responsible for a step in the pathway

• different from sulfa drugs

• Two drugs can work synergistically

  • utis

cell integrity

Polymyxin 13

• Binds to Gram neg. cell membrane

• alters permeability-leakage

• Bides eukaryotic membrane so only used topically

• first aid ointments

Daptomycin

• Inserts bacterial Cytoplasmic membrane

• Gram pos.

• cannot penetrate Gram neg outer membrane

Determining Drug susceptibility

not good practice to keep trying drugs

until they work or giving a bunch at once

Each ineffective or (needed drug given uneceisurity increases risk of side effects, allergic reactions, antibiotic resistance in bacterial strains, altered normal flora and unfavorable drug interactions with each other

Best to determine the susceptibility of pathogen to a drug before administering

• not always practical

Resistance to Antimicrobial Drugs

Many stains are now resistant to antibiotic

more than 90 % of staphoblocuss aureus trains are resistant

• Due to use and misuse of antibiotics

Mechanisms of Acquired Resistance

Drug inactivating enzymes

• can inactivate drugs by modifing them

Alteration in Target Molecule

• minor changes can prevent antimicrobial drugs from binding

Decreased uptore of Drug

• change in porins of outer membrane in Gram Neg bacteria altering permeability and preventing drug uptake

Increased Elimination of Drug

• Efflux pumps transport harmful compounds out of bacteria.

• Bacteria can increase expression of these pumps creating increased capacity to pump out drugs.

• changes affect which drugs it can pump out

Acquisition of Resistance

spontaneous Mutation

• mutations occur spontaneously at a low rate but Selective pressure can result in rapid population change from one spontaneous mutation

• streptomycin binds to a ribsomal protien resistance results from just one base pair change in the ribosomal protien gene

• Developing resistance through this method is more difficult when the drug has multiple targets or binding sites

• can be effective to use a drug like Streptomycin with another drug

Gene Transfer

• Genes encoding for resistance can move between bacterium of different strains, species or even genera

  • Ex: Conjugative transfer of R plasmids, Transformation

• Resistance encoding genes can come from spontaneous mutations or from a microbe that naturally produces the antibiotic

Enterococci

• group of bacteria which is a part of out normal intestinal flora but also a common cause of wealth care infections

• Have some intrinsic resistance-PBP have flow affinity for B-lactam antibiotics, they have plasmid resistance genes-transferable

staphylococcus

• common healthcare infection

• Became penicillin-resistant with penicillinase gene acquisition.

  • could be treated with penicillinase resistant methicillin

• Developed PBP with low affinity for B-lactam drugs

  • MRSA

• usually can be treated by vancomycin.

  • strains require extremely high dose or all completely resistant

streptococcus pneumonia

• the normal cause of adult pneumonia

  • sensitive to penicillin

• Isolates are resistant to penicillin

  • have PBP with decreased affinity

• new versions of PBP due to acquisition of chromosomal DNA from another streptococcus species

Mycobacterium tuberculosis

• long and complicated treatment

  • 2 drugs for 6 months

  • becoming more complicated

• Patients often do not comply perfectly with the regimen

  • resistance

• MDR-TB -multiple drug-resistant TB

• EDR-TB-multiple drug-resistant TB

slow emergence and spread

physicians and health care workers

• identify infection and pressurize antibiotics

• educate patients to help with compliance

Patients

• follow instructions completely

Educate Public

• people need to know what antibiotics do and don't do

• know why they are given treatment regimens and why it is important to follow them

• Taking antibiotics without a bacterial Infection only serves to affect normal flora, select for resistance, and become a reservoir for resistance genes

Global Impact

• resistance can transverse the globe quickly

• In many countries, Antibiotics are Available without prescription

• Antimicrobials in animal feed linked to resistant salmonella infections