Definitions Bacteremia: Presence of bacteria in the blood Under normal circumstances, the blood is a...

Definitions

• Bacteremia: Presence of bacteria in the blood• Under normal circumstances, the blood is a sterile

environment

Systemic Inflammatory Response Syndrome (SIRS)

• An inflammatory response, to a wide variety of clinical insults, characterized by two or more of the following:– Temperature greater than 38 oC (100.4 oF)– Heart rate greater than 90 beats per min– Respiratory rate greater than 20 breaths per min– White blood cell count greater than 12,000/L

Sepsis

Sepsis is a systemic inflammatory response to a documented infection

In addition to preceding criteria, at least one of the following must be present:

Alteration in mental stateHypoxemia (lower pressure of oxygen in blood)Elevated plasma lactate

Allergic Responses to Antibiotics

• Uticaria: A skin rash involving dark red itchy bumps.

Allergic Responses

• Anaphylaxis: A severe, life-threatening allergic response, having many potential manifestations, including loss of consciousness, labored breathing, swelling of the tongue, low blood pressure, etc.

Shock

• Shock is characterized by low blood pressure (hypotension) and tachycardia

• Septic shock is a result of the infection itself (bacteremia, sepsis).

• Anaphylactic shock is an allergic response to a foreign agent (antibiotic, bee sting, etc.)

Vancomycin

Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

Peptide Linkages

Carbohydrate

Discovery

Vancomycin was discovered in a soil sample sent to the pharmaceutical company Eli Lilly by a missionary in Borneo in the 1950’s.

Vancomycin Mechanism of Action• http://student.ccbcmd.edu/courses/bio141/lecgui

de/unit2/control/vanres.html• Link

Penicillin Mechanism of Action (review)

http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html

Bacterial Cell Wall Synthesis (review)

•http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html

http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.html



http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html

http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html

Mechanism of Action of Vancomycin

Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall.

Vancomycin Uses

• Vancomycin is used to treat aerobic Gram + bacteria, including MRSA and strains of penicillin-resistant Streptococcus pneumoniae

• Vancomycin is most often administered intravenously• Vancomycin can also be used to treat anearobic Gram

+ bacteria, including Clostridium difficile (in the case of a GI infection, Vancomycin can be administered orally).

• Vancomycin cannot be used to treat Gram – bacteria, since the large size of the vancomycin molecule prohibits its passing of the outer membrane.

Vancomycin Resistance

• Some Enterococci have developed resistance to vancomycin (Enterococcus faecium and Enterococcus faecalis).

• These bacteria are called Vancomycin Resistant Enterococci (VRE)

• The mechanism of resistance involves the transformation of the D-Ala-D-Ala linkage in the peptide side chain into D-Ala-D-Lac (i.e. replacement of the NH2 group by an OH group)

• This terminal linkage is still recognized by the essential PBP’s (so the cell wall can still be constructed), but is not recognized by vancomycin (thus resulting in resistance).

Gram-positive bacteria

Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci.

Gram-negative bacteria

Anaerobic bacteria Clostridium spp. Other Gram-positive anaerobes.

Atypical bacteria

Antimicrobial Activity of Vancomycin

Daptomycin

• Daptomycin is called a lipopeptide antibiotic • Approved for use in 2003• Lipid portion inserts into the bacterial cytoplasmic membrane where it

forms an ion-conducting channel.• Marketed under the trade name Cubicin

Lipophilic Tail

Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner

Step 2: Daptomycin oligomerizes, disrupting the membrane

Step 3: The release of intracellular ions and rapid death

Link

Uses of Daptomycin (Cubicin)

• Daptomycin is active against many aerobic Gram-positive bacteria

• Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE)

• Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.

• Primarily been used to treat skin and soft tissue infections (complicated skin and skin structure infections, including MRSA).

• Also approved for S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis

• Poor activity in the lung, thus not used for pneumonia

• Cubicin (Daptomycin) is administered intravenously.

• It is not orally bioavailable.


Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.


Anaerobic bacteria

Some Clostridium spp.

Atypical

Antimicrobial Activity of Daptomycin

Rifamycins

• Rifampin is the oldest and most widely used of the rifamycins

• Rifampin is also the most potent inducer of the cytochrome P450 system•

The Rifamycins

Rifampicin (Rifampin)

Rifabutin(Mycobutin)

Rifapentine(Priftin)

Rifaximin(Xifaxan (US), Spiraxin (EU))

• Therefore, Rifabutin (brand name Mycobutin) is favored over rifampin in individuals who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking

• Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.

Mechanism of Action of Rifampin

• Rifampin inhibits transcription by inactivating bacterial RNA polymerase

• Resistance develops relatively easily, and can result from one of a number of single mutations in the baqcterial gene that encodes RNA polymerase.

• Therefore, Rifampin is rarely used as monotherapy (i.e. not used as a single agent) but usually combined with other antibiotics

Uses of Rifampin

• Used, in combination with other drugs, to treat Mycobacterium tuberculosis

• Used to treat some Staphylococcal infections.

• Rifampin and the other rifamycins are orally bioavailable.


Staphylococci


Haemophilus influenzae, Neisseria meningitidis

Anaerobic bacteria

Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae.

The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally.

Aminoglycosides

The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents.

Aminoglycoside Mechanism of Action

• Aminoglycosides bind to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis (translation)

• Link• http://www.microbelibrary.org/microbelibrary/files/

ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

• http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

• Link• Link

The ribosome target of aminoglycosides is a combination of RNA (below) and proteins

Uses of Aminoglycoside Antibiotics

• Unlike vancomycin, the aminoglycosides have excellent activity against Gram – aerobic bacteria

• Their extensive positive charge enables them to bind to and penetrate the negatively charged outer membrane and get into the periplasm

• They are further transported into the cytoplasm by a bacterial transport system.

Lipopolysaccharide is Part of the Outer Membrane of Gram Negative

Bacteria

• Bacterial lipopolysaccharides are toxic to animals. When injected in small amounts LPS or endotoxin activates several host responses that lead to fever, inflammation and shock.

• Endotoxins may play a role in infection by any Gram-negative bacterium. The toxic component of endotoxin (LPS) is Lipid A. The O-specific polysaccharide may provide for adherence or resistance to phagocytosis, in the same manner as fimbriae and capsules.

• The O polysaccharide (also referred to as the O antigen) also accounts for multiple antigenic types (serotypes) among Gram-negative bacterial pathogens.

• Thus, E. coli O157 (the Jack-in-the-Box and Stock Pavillion E. coli) is #157 of the different antigenic types of E. coli and may be identified on this basis.

Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target:

(1) Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium.

(2) Modification of the aminoglycoside prevents binding to the ribosome.

(3) Mutations within the ribosome prevent aminoglycoside binding.

The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as

Neomycin (topical, oral).

Aminoglycosides

Streptomycin

Streptomycin was the first aminoglycoside to be discovered (1944) and it still valuable (in combination with other antibacterial agents) in the treatment of multidrug resistant tuberculosis (although not a first line drug for tuberculosis)

Aminoglycosides

Gentamicin

•Gentamicin is most commonly used of the aminoglycosides•Active against aerobic Gram-negative infections (and sometimes Gram positive)•Can be used synergistically, together with a cell wall targeting agent (e.g. a penicillin)•Available in parenteral, opthalmic, and topical formulations

Aminoglycosides

Tobramycin•Tobramycin has better activity against Pseudomonas aeruginosa than does gentamicin•Tobramycin may be given either intramuscularly or intravenously•It is also administered by inhaler, particularly useful for individuals with cystic fibrosis (frequently contract P. aeruginosa infections)

Amikacin

• Amikacin has the broadest antimicrobial spectrum of the aminoglycosides

• It is more resistant to aminoglycoside-inactivating enzymes than the other aminoglycosides

• It is often used in hospitals where gentamicin- and tobramycin-resistant microorganisms are prevalent

Neomycin

• Neomycin is widely used for topical administration• Like other aminoglycosides, it is not absorbed well

orally, and is used to prepare the bowel for surgery.


Used synergistically against some: Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes


Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa

Anaerobic bacteria

Atypical bacteria

Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex.

The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

Macrolides and Ketolides

The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides.

Chemical Definitions

• Macrolide = macrocyclic lactone (cyclic ester)

• Macrolide antibiotics usually have ring sizes of 14, 15, or 16 atoms

Ester LinkageCladinose Sugar

Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

Mechanism of Action of Macrolide Antibiotics

• Macrolides bind tightly to the 50S subunit of the bacterial ribosome, thus blocking the exit of the newly synthesized peptide

• Thus, they are interfering with bacterial translation• http://www.microbelibrary.org/microbelibrary/files/

ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

• http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

• Link• Link

Uses of Macrolide Antibiotics

• Active against a broad range of bacteria

• Effective against some stphylococci and streptococci, but not usually used for MRSA or penicillin-resistant streptococci

• Most aerobic Gram- bacteria are resistant

• Active against many atypical bacteria and some mycobacteria and spirochetes

The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).

ErythromycinClariithromycin

Erythromycin reactions under acidic conditions

Clarithromycin substitutes a methoxy group for the hydroxy and improves

acid stability

Erythromycin(14 membered ring)

Clariithromycin(14 membered ring)

Hydroxy group

Methoxy group

Azithromycin(15 membered ring)

Link

LInk

Insertion of ‘N’ into the ring


Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus.


Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis

Anaerobic bacteria

Atypical bacteria

Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp.

Mycobacteria Mycobacterium avium complex, Mycobacterium leprae.

Spirochetes Treponema pallidum, Borrelia burgdorferi.

The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).

Uses of Telithromycin (a ketolide)

• Telithromycin is approved for use against bacterial respiratory infections

• Active against most strains of Streptococcus pneumoniae, including penicillin- and macrolide-resistant strains

• Also active against more strains of Staphylococci

• Only available in oral formulation

Telithromycin: A ketolide(14 membered ring)

Cladinose sugar replaced by ketone


Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus


Some Haemophilus influenzae, Bordetella pertussis

Anaerobic bacteria

Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila

The related ketolide class consists of Telithromycin (oral).

The Tetracycline Antibiotics

The structure of tetracycline

Tetracycline Antibiotics

Tetracycline Tigecycline

Doxycycline

Mechanism of Action of the Tetracycline Antibiotics

• The tetracyclines bind to the 30S subunit of the bacterial ribosome and prevent binding by tRNA molecules loaded with amino acids.

• http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/tetres.html

Uses of the Tetracycline Antibiotics

• Main use is against atypical bacteria, including reckettsiae, chlamydiae, and mycoplasmas

• Also active agains some aerobic Gram-positive pathogens and some aerobic Gram-negative bacteria


Some Streptococcus pneumoniae


Haemophilus influenzae, Neisseria meningitidis

Anaerobic bacteria

Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum

Atypical bacteria Rickettsia spp. Chlamydia spp.

The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral)

Tigecycline


Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes


Haemophilus influenzae, Neisseria spp. Enterobacteriaceae

Anaerobic bacteria

Bacteroides fragilis, Many other anaerobes

Atypical bacteria Mycoplasma spp.

The antimicrobial activity of Tigecycline (parenteral)

Chloramphenicol

Mechanism of Action of Chloroamphenicol

• Binds to the 50S subunit of the bacterial ribosome, where it blocks binding of tRNA

Uses of Chloramphenicol

• Severe toxicity limits utility• The most serious side effect of chloramphenicol

treatment is aplastic anaemia (a condition where bone marrow does not produce sufficient new cells to replenish blood cells)

• This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect.

• The effect usually occurs weeks or months after chloramphenicol treatment has been stopped.

Uses of Chloramphenicol

• However, despite its toxicity, chloramphenicol has a wide spectrum of activity, that includes many aerobic Gram-positive, Gram-negative, anaerobic, and atypical bacteria


Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae


Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp.

Anaerobic bacteria

Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria

Atypical bacteria Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp.

The Antimicrobial Activity of Chloramphenicol

Clindamycin

Mechanism of Action of Clindamycin

• Clindamycin binds to the 50S subunit of the ribosome to inhibit protein synthesis

Uses of Clindamycin

• Clindamycin is a member of the lincosamide series of antibiotics

• Main utility is in treatment of Gram-positive bacteria and anaerobic bacteria

• Active against staphylococcus, including some strains of MRSA

• Not useful against Gram-negative bacteria

Toxicity of Clindamycin

• Clindamycin kills many components of the gastrointestinal flora, leaving only Clostridium difficile

• This can result in overgrowth by C. difficile, which is resistant


Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus


Anaerobic bacteria

Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes.

Atypical bacteria

The Antimicrobial Activity of Clindamycin (both oral and parenteral)

Streptogramins

Mechanism of Action of Streptogramins

• Dalfopristin inhibits the early phase of protein synthesis in the bacterial ribosome and quinupristin inhibits the late phase of protein synthesis. The combination of the two components acts synergistically and is more effective in vitro than each component alone.

• Link

Uses of the Streptogramins

• Have activity against Gram positive aerobic bacteria

• Including MRSA, penicillin-resistant Streptococcus pneumoniae and some VRE (active against vancomycin resistant Enterococcus faecelis, but not Enterococcus faecium)

• The Quinupristin/Dalfopristin mixture is marketed as Synercid


Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci.


Anaerobic bacteria

Atypical bacteria

The Antimicrobial Activity of Quinupristin/Dalfopristin (parenteral)

The Oxazolidinones

The structure of Linezolide

• Binds to the 50S subunit and prevents association of this unit with the 30S subunit.

Mechanism of Action of the Oxazolidinones

• Binds to the 50S subunit and prevents association of this unit with the 30S subunit.

• http://student.ccbcmd.edu/courses/bio141/lecguide/unit6/genetics/protsyn/translation/oxazolres_anim.html

Uses of the Oxazolidinones

• Has excellent activity against most aerobic Gram-positive bacteria, including MRSA and VRE.

• Only oxazolidonone on the market now is Linezolid, which is both oral and intravenous.


Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.


Anaerobic bacteria

Atypical bacteria

The Antimicrobial Activity of Linezolid (both oral and parenteral)

The Sulfa Drugs

OCH3

OCH3

OCH3

H2C

N

N

NH2

H2N

Sulfamethoxazole Trimethoprim

•Most commonly used sulfa drug is a mixture of the sulfa drug Sulfamethoxazole and Trimethoprim

•These two drugs work in synergy, with the combination being superior to either drug alone.

• This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX

Mechanism of Activity of Sulfa Drugs

• Trimethoprim-sulfamethoxazole works by preventing the synthesis of tetrahydrofolate (THF), an essential cofactor for the metabolic pathways that generate deoxynucleotides, the building blocks of DNA.

Tetrahydrofolic Acid Biosynthetic Pathway

• In the first step of the pathway, the sulfonamides are mistaken for the natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a competitive inhibitor of this enzyme

• In a later step, the trimethoprim acts as a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase

The Target of Trimethoprim is Dihydrofolate Reductase (DHFR)

Inhibitors of Dihydrofolate Reductase (DHFR)

H2N

OH

O

Sulfamethoxazole p-Aminobenzoic Acid

Structural Resemblance of Sulfamethoxazole and p-Aminobenzoic Acid

Another sulfa drug is Dapsone, which is used to treat Mycobacterium leprae

S

NH2H2N

OO

Dapsone

Structural Comparison of Two Sulfa Drugs


Some Sreptococcus pneumoniae, Some Staphylococci, Listeria monocytogenes


Some Haemophilus influenzae, Some Enterobacteriaceae

Anaerobic bacteria

Atypical bacteria

Mycobacteria (Dapsone)

Mycobacterium leprae

The Antimicrobial Activity of the Sulfa Drugs

The Fluoroquinolones

N N

O

Et

F CO2H

HN

N N

O

F CO2H

HN

N N

O

F CO2H

N OCH3

N N

O

F CO2H

N OCH3

Norfloxacin(Noroxin)

Ciprofloxacin(Cipro)

Ofloxacin(Floxin)

Levofloxacin(Maxaquin)

N N

O

F CO2H

NH O

Gatif loxacin(Tequin)

H3C

N N

O

F CO2H

NH O

Moxifloxacin(Avelox)

H3C

Fluoroquinolones

Mechanism of Action: Quinolones

• Quinolone antibiotics inhibit bacterial DNA gyrase (Gram negative bacteria) or Topoisomerase IV (Gram positive bacteria)

• Link

Uses of the Quinolone Antibiotics

• Urinary Tract Infections: fluoroquinolones are more effective than trimethoprim-sulfamethoxazole

• Prostatitis

• Respiratory tract infections

• Gastrointestinal and Abdominal Infections


Some Staphylococcus aureus, Streptococcus pyogenes, Virdans group streptococci, Streptococcus pneumoniae


Neisseria spp. Haemophilus influenzae

Many Enterobacteriaceae, Some Pseudomonas aeruginosa

Anaerobic bacteria

Some clostridia spp, Some Bacteroides spp.

Atypical bacteria Chlamydia and Chlamydophilia, Mycoplasma pneumoniae, Legionella spp

Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium leprae

Antimicrobial Activity of the Quinolones (oral)

Metronidazole (Flagyl)

Metronidazole is used in the treatment of infections caused by anaerobic bacteria

Metronidazole Mechanism of Action

Metronidazole is a prodrug. It is converted in anaerobic organisms by the redox enzyme pyruvate-ferredoxin oxidoreductase. The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.

Mechanism of Action of Metronidazole

• Metronidazole is selectively taken up by anaerobic bacteria and sensitive protozoal organisms because of the ability of these organisms to reduce metronidazole to its active form intracellularly.

Systemic metronidazole is indicated for the treatment of:

• Vaginitis due to Trichomonas vaginalis (protozoal) infection in both symptomatic patients as well as their asymptomatic sexual contacts;

• Pelvic inflammatory disease in conjunction with other antibiotics such as ofloxacin, levofloxacin, or ceftriaxone

• Protozoal infections due to Entamoeba histolytica (Amoebic dysentery or Hepatic abscesses), and Giardia lamblia (Giardiasis) should be treated alone or in conjunction with iodoquinol or diloxanide furoate

• Anaerobic bacterial infections such as Bacteroides fragilis, spp, Fusobacterium spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp, or any other anaerobes in intraabdominal abscess, peritonitis, empyema, pneumonia, aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain abscess, bone and joint infections, septicemia, endometritis, tubo-ovarian abscess, or endocarditis

• Pseudomembranous colitis due to Clostridium difficile

• Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease

• Prophylaxis for those undergoing potentially contaminated colorectal surgery and may be combined with neomycin



Anaerobic bacteria

Bacteroides fragilis, Clostridium spp. Most other anaerobes

Atypical bacteria

Antimicrobial Activity of Metronidazole (both oral and intravenous)

Antimicobacterial Agents

• Mycobacterial infections are very slow progressing

• Many antibiotics have poor activity against slow growing infections

• Mycobacteria must be treated for a long time, and therefore, may readily develop resistance to a single antibiotic

• Typically, several antibiotic agents are used simultaneously

Antimycobacterial Agents

RifampinPyrazinamide

NH

HN

CH2OH

CH2OH

Ethambutol

Mycobacterial Infections

http://www.nature.com/nrmicro/animation/imp_animation/index.html

http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html

Mycolic Acids provide protection

• Mycolic acids are long fatty acids found in the cell envelope of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species.

• The presence of mycolic acids gives M. tuberculosis many characteristics that defy medical treatment. They lend the organism increased resistance to chemical damage and dehydration, and prevent the effective activity of hydrophobic antibiotics. In addition, the mycolic acids allow the bacterium to grow readily inside macrophages, effectively hiding it from the host's immune system.

Mycobacterium Cell Wall

Mechanism of Action of Anti-Mycobacterial Antibiotics

• Rifampin is an inhibitor of RNA polymerase

• Isoniazide inhibits the synthesis of mycolic acid

Mechanism of Action of Isoniazid

Isoniazid is a produg, that is activated by a mycobacterial peroxidase, called KatG to form a reactive free radical, which, in turn, reacts with NADH to form a covalent adduct. The reactive (isoniazid-derived) species is probably an acyl radical (shown)

isoniazid

NADH

N

O

Mechanism of Action of Isoniazid

This isoniazid-NADP adduct then forms a complex with bacterial enoyl reductase (InhA),an enzyme responsible for reducing double bonds during fatty acid synthesis

• Pyrazinoic acid inhibits the enzyme fatty acid synthetase I (FAS I), which is required by the bacterium to synthesise fatty acids.

• Ethambutol disrupts the formation of the cell envelope by interfering with the enzyme that forms the arabinogalactan polysaccharide (called arabinogalactan transferase)

Arabinogalactan

• Arabinogalactan is a biopolymer consisting of arabinose and galactose monosaccharides

D-Galactose

Arabinogalactan-mycolic acid adduct

Targets of First Line anti-TB Drugs

Overview of anti-mycobacterial drugs

Assigned Reading: • Antibiotic Basics for Clinicians, by Alan R. Hauser, pp. 33—99• Kirkpatrick Peter; Raja Aarti; LaBonte Jason; Lebbos John Daptomycin. Nature reviews. Drug discovery (2003), 2(12), 943-4.• Ammerlaan, H. S. M.; Bonten, M. J. M. Daptomycin: graduation day. Clinical Microbiology and Infection (2006), 12(Suppl. 8),

22-28. • Baltz, Richard H.; Miao, Vivian; Wrigley, Stephen K. Natural products to drugs: Daptomycin and related lipopeptide antibiotics.

Natural Product Reports (2005), 22(6), 717-741. pp. 717-722, 725-726.• Baltz Richard H Daptomycin: mechanisms of action and resistance, and biosynthetic engineering. Current opinion in chemical

biology (2009), 13(2), 144-51. Journal code: 9811312.• Clay Kimberly D; Hanson John S; Pope Scott D; Rissmiller Richard W; Purdum Preston P 3rd; Banks Peter M Brief

communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Annals of internal medicine (2006), 144(6), 415-20.

• Zeitlinger, Markus; Wagner, Claudia Christina; Heinisch, Birgit. Ketolides - the modern relatives of macrolides : the pharmacokinetic perspective. Clinical Pharmacokinetics (2009), 48(1), 23-38.

• Vicens, Quentin; Westhof, Eric. RNA as a drug target: The case of aminoglycosides. ChemBioChem (2003), 4(10), 1018-1023.

• Wilson, Daniel N.; Nierhaus, Knud H. The oxazolidinone class of drugs find their orientation on the ribosome. Molecular Cell (2007), 26(4), 460-462.

• Marchese, A.; Schito, G. C. The oxazolidinones as a new family of antimicrobial agent. Clinical Microbiology and Infection (2001), 7(Suppl. 4), 66-74.

• Asaka, Toshifumi; Manaka, Akira; Sugiyama, Hiroyuki. Recent developments in macrolide antimicrobial research. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2003), 3(9), 961-989. [READ ONLY PP. 961-966 AND 981-983]

• Zhanel, George G.; Homenuik, Kristen; Nichol, Kim; Noreddin, Ayman; Vercaigne, Lavern; Embil, John; Gin, Alfred; Karlowsky, James A.; Hoban, Daryl J. The glycylcyclines: a comparative review with the tetracyclines. Drugs (2004), 64(1), 63-88. [Read pp. 64-72]

Homework Questions:

1. To which site on the ribosome do the aminoglycoside antibiotics bind?

2. A high level of aminoglycoside resistance is known to result from the A1408G mutation in bacterial ribosomes. A potential solution would be to design aminoglycosides that can bind more tightly to this mutation. Why can’t this be achieved?

3. Discuss the advantages and the disadvantages of using RNA as a drug target.

4. The activity o f daptomycin is highly dependent on which alkaline earth metal? What is the function of this metal in the mechanism of action (MOA) of daptomycin?

5. At which ribosomal site do the oxazolidinones bind? What accounts for their side effects in patients undertaking prolonged treatment with these drugs?

6. Why is azithromycin currently considered one of the best of the macrolides?

7. Explain how tetracyclines gain access to the cytoplasm of Gram-negative bacteria.

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