Transcript 11 Antibiotics

ANTI-BACTERIAL Compounds
Germicide / antiseptic on skin & disinfectant on things
External use – most are oxidants:
Cl2, O3, I2, NaOCl, H2O2, KMnO4, Chloramine-T
CH3
Na
SO2 N
Cl
Cl
HO
Phenol(s)
COOMe
O
R
Cl
Chloramine-T
OH
OH
Cl
Triclosan
Methyl salicylate
Phenols: generally toxic through skin but <1.5 % is tolerable
egs. Lysol (= p-cresol), TCP (= trichlorophenol), phenol (carbolic
acid, R=H), Triclosan
Listerine contains menthol, thymol, methyl salicylate and eucalyptol
Quaternary Ammonium Compounds - Mouthwash - R4N+ X+
N (CH2)15CH3
CH3
+
OCH2CH2N (CH2)11CH3 Br
CH3
Br -
Cetyl pyridinium bromide
(Life, Safeway brands, etc.)
Domiphen bromide
NH
Cetrimonium bromide
is (CH3)3N+(CH2)15CH3 Br= cetrimide
Cl
NH
NH
NH
NH
(CH2)6
NH
NH
NH
Chlorhexidine –
for gingivitis
NH
NH
Cl
INTERNAL USE:
Bacteria divided into Gram +ve and Gram -ve groups:
Crystal violet stain turns both purple but only Gram +ve reamin so
after I2 treatment and an acetone-alcohol-water wash
Gram +ve have thick walls with no outer membrane and trap stain
egs.
Streptococcus, Staphylococcus, Pneumonococcus
Game –ve have thin walls with inner and outer membranes and do
NOT retain the stain
egs.
Meningitis, Salmonella, E. Coli, Pseudomonas
TB (tuberculosis, consumption)
(Mycobacterium tuberculosis)
destroys lung tissue, still kills ca. 1-2M / y
WHO estimates 1/3 pop of earth carries TB bacterium
TB vaccine essentially wiped out TB in the West but ca. 424K/y
drug resistant cases (ca. 30K/y are VERY drug resistant)
UVic case February 2009
rifampicin and isoniazid are most common treatment but procedure
is long and many cut it short: as a result 1.2% of cases are resistant
Serious concerns that TB could reappear in West:
No new drugs for 40 years but ~ 30 now under study
A new Johnson &Johnson drug (R207910)
is under trials that inhibits ATP synthase
Bayer is in trials with moxifloxacin
Novartis is in trials with a nitroimidazole
OH
Br
N
R207910
O
N
THE SULFA DRUGS: effective against most Gram +ve, some
Gram –ve
N
H2N
N
N
N
NH
CONH
CHCH2CH2COOH
OH
COOH
H2N
COOH
FOLIC ACID
PABA p-aminobenzoic acid
We eat folic acid; bacteria make it from PABA: we can fool them
using sulfanilamide so they die of vitamin deficiency
H2N
R=
SO2NHR
N
a sulfanilamide
SO2 NH
N
S
Sulfapyridine Sulfadiazine Sulfathiazole
N
H2 N
N
N
O
sulfamethoxazole common in Canada
PENICILLINS (Narrow spectrum antibiotics)
History:
Original mould: penicillin notatum (pencil shapes) discovered by
Fleming while working on staph bacteria, left cover plate off and
noticed bacteria did not grow near mould
Flory (Oxford, 1940) found way to extract
penicillin out of mould, tried it on London
policeman with blood poisoning from
shaving cut.
Wartime: needed to make much more,
(used bed pans in Oxford to grow mould)
so in June 1941 took production to USA
(15,000 gallon vessels)
Mould now: penicillin chrysogenum
found on a cantaloupe in Peoria, Illinois in
1943 gave better yields and is used to
make Pen-G
Penicillins: general formula includes the b-lactam ring
RCONH
S
CH2 Pen
Pen-G has R- =
N
O
Pen-G
COOH
OH
Pen
CH3
OCH2-Pen
Pen-V
H2N
Pen
Ampicillin
O N
H2N
Cl
Pen
Amoxicillin
Cloxacillin
You can make those other than Pen-G by feeding the mould the
appropriate acid, RCOOH
Pen-G has to be injected: 600-2400 mg/day IV in 3-4 doses
Useful against most GRAM +ve plus pneumonia, meningitis,
gonorrhea, gangrene, bone infections
Others can be taken orally:
Pen-V: 300mg per 8h, first oral one
Amoxicillin: most common, 250-500 mg per 8h
Ampicillin: best for urinary tract
Cloxacillin: approved for some resistant bacteria
Many people are allergic to Penicillins (especially G) – can
lead to death!
HOW PENICILLINS WORK:
b-lactam ring binds to a transpeptidase enzyme responsible for
forming the cross links in the peptidoglycan layer (bacterial cell
walls):
as the cell grows it needs to constantly break these layers: If it can’t
expand, the cell bursts and dies
BUT some bacteria have Penicillinase, an enzyme that cleaves the blactam ring and allows normal wall formation: resistant
Five Penicillins are more
resistant to Penicillinase:
mainly reserved for Staph
infections (egs. Nafcillin
and Methicillin)
Pen
Pen
OEt
R=
nafcillin
MeO
OMe
methicillin
CEPHALOSPORINS: from mould found in sewage (Sardinia 1950’s)
R-CONH
S
N
O
Z
COOH
R=
R=
H2N
Ceph
+
N
Ceph
internal -COO
Z=Cl
a cephalosporin
Cefachlor (Ceclor)
250 mg/8h, 2g/day max
H2N
S
N
Z=
Ceph
N
OCH3
Cefepime (Maxipime)
1 g/12h for 10 days
Very popular (~2B$/y)
more effective than penicillins against Gram -ve types
CPS lists 16 in use all start with CefNot affected by penicillinase but a cephalosporinase has now
emerged
WIDE SPECTRUM ANTIBIOTICS: MYCINS and TETRACYCLINES
Streptomycin (from soil) in 1947 –
stops cell division,
shuts down protein/RNA synthesis
Too toxic for use, then last resort for TB
Also from soil: the tetracyclines:
OH
O
OH O
OH
CONH2
OH
X
OH Z
N(CH3)2
tetra-cyclo = 4 rings
(A,B,C,D)
Chlorotetracycline
(Aureomycin)
X=Cl, Z=OH
Tetracycline (Terramycin,
Ambramycin,.....)
X=H, Z=OH
OH
More common ones now:
O
OH O
OH
CONH2
OH
X
OH Z
N(CH3)2
Doxycycline (Vibramycin)
X=H, Z=OH, no OH in ring B
Minocycline (Klinomycin)
X=NMe2, Z=H, no OH or Me in ring B
Demeclocycline (Declomycin) X=Cl, Z=H, no Me in ring B
Doses: 250-600 mg/6h
They inhibit protein synthesis by binding to the ribosome,
Kill most bacteria = broad spectrum
including intestinal bacteria, so side effect is DIARRHEA
Eat pro-biotic yogurt when on this (and shortly after stopping)!!
Was used against Legionnaire’s Disease (Chicago 1976)
Ca salts, antacids bind to them: avoid milk and antacids
Side effects:
browning of teeth (acne treatment for teens)
photosensitive skin
reduced effectiveness of birth control pills
Mostly excreted unchanged – high levels can be found in sewage!
Aside on Legionnaire’s disease: hundreds staying at one hotel fell ill (34
died) during the 1976 American Legion Convention in Chicago - discovered that
the pneumonia-like illness was caused by a previously unknown bacterium, now
known as Legionella pneumophillia. Turns out the bacteria proliferates in warm,
stagnant water, in this case in the hotel air conditioning system. Subsequent
outbreaks have occurred in 1999 (Netherlands flower show, 34 died), 2001 (Spain,
hospital cooling tower, 6 died) and 2002 (UK, Art Center cooling tower, 7 died)
AMINOSUGARS (AMINOGLYCOSIDES)
ERYTHROMYCIN
CLINDAMYCIN (Dalacin)
O
O
OH
N
Cl
NH
HO
O HO
O
O
O
HO
NMe 2
O
OH
OMe
SMe
OH
OH
Very widely used
allergic reactions rare
More toxic
usually only for more
serious infections
cross placenta and go in to breast milk
Dose: ~ 1 g/day in 2-4 doses; up to ~4 g/day in more serious cases
VANCOMYCIN
Last resort for many staph
types:
interferes with wall synthesis
VRE = Vancomycin resistant
enterococci (opportunistic gut
infection) - in Canadian
hospitals (see chart at right)
NH2
O
DAPTOMYCIN
O
O
O
NH
O
NH
HO
O
O
NH
NH
O
NH
O
NH
NH
(CH2 )8 CH3
NH
O
HN
HN
NH
HOOC
H2 N
HOOC
HOOC
O
O
HOOC
NH
O HN
NH
O
NH2
O
used against VRE and methicillin resistant staph (MRSA)*
(stops synthesis of cell membranes)
* ’flesh eating disease’ 30% mortality
QUINOLONES - CIPRO
Quinolones are synthetic, made first in 1987
They block bacterial DNA replication by stopping the re-coiling of
new strands, make KNOTS instead
CIPROFLOXACIN: most active broad spectrum antibiotic available
(Anthrax scare)
Sales ~ 2B$/y
especially useful for lung infections, bones, urinary tract (oral or IV)
NH
N
N
N
F
HO2C
O
Related:
Norfloxacin (Noroxin)
Et in place of cyclopropyl
Some newer ones:
F
N
NOMe
N
O
N
N
HOOC
NH
F
HOOC
HOOC
N
N
CH 2NH 2.HO 3SMe
N
F
O
N
F
F
O
O
Levofloxacin
LEVAQUIN
Trovafloxacin
TROVAN
Gemifloxacin
wide use for TB
Others: moxifloxacin; gatifloxacin; ofloxacin
Trovan (2 x 200mg/day): In Canada about 360,000 pneumonia cases
per year, still 7000 deaths
Some strains of staph which are Vancomyin and Methicillin
resistant are now resistant to Cipro
Need to keep making newer classes:
2-Pyridones
and
Oxazolidinones
O
F
H2N
N
COOH
O
N
N
F
NHCOCH3
O
O
Linezolid (ZYVOXAM)
Antagonize enzymes: Bind the bacterial ribosome, shuts down
protein synthesis
NEWEST APPROACH
EFFLUX PUMP BLOCKERS
Some resistant strains pump antibiotic out of the cell:
these block that pump action
MICROCIDE have found a peptide that stops pseudomonas
effluxing fluoroquinolones = drug ca. 8x more effective
2005: FDA granted fast track status
to intravenous iclaprim for the
treatment of complicated skin and
skin structure infections (cSSSI) –
resistant staph
ANTI-FUNGALS
Tolnaftate, Tinactin, Pitrex
Fungistop, Triactin
topical only, inhibits steroid
biosynthesis
N-C-O
S
OMe
O OMe
O
O
MeO
Cl
Griseofulvin (Fulvicin, Grisovin, Grisactin)
hair and nail infections
orally for ‘ringworm’
made by mould penicillin griseofulvin: disrupts the microtubules
Not if pregnant:
Not with alcohol:
teratogen
tachycardia
NYSTATIN (mycostatin)
especially for yeast (candida) infections
(mouth, throat, vagina, underarms....)
Method of action: binds to ergosterol, the main component of the
fungal cell membrane. If present in sufficient concentrations, it
forms a pore in the membrane that leads to K+ leakage and death
of the fungus.
(mammals do not have ergosterol-based cell membranes)
MONISTAT (miconazole)
Vaginal yeast infections: inhibits biosynthesis of triglycerides (fats),
phospholipids, steroids and damages the fungus cell wall
Used topically as 2-3% cream
N
N
CH2 CH OCH2
Cl
Cl
Cl
Cl
N
F
N
OH
F
OH
O
N N
OH
N
terbinafine
(an allylamine)
H2 NSO2
Cl
N
Chlorphensin
O
N
N N
Cl
COOH
NH
Cl
Fluconazole
furosemide
Clotrimazole
N
N
O
N
N
N
N
N
O
O
N
N
O
Cl
N
N
Cl
O
Itraconazole
N
Cl
N
Cl
Cl
O
O
O
Cl
Cl
Oxiconazole
ketoconazole
OTHER ANTIFUNGALS
Terbinafine
Ketoconazole
Fluconazole
Itraconazole
Clotrimazole
Oxiconazole
Chlorphenesin
N
[LAMISIL]
[NIZORAL] cream, shampoo, tablets
[DIFLUCAN] capsules
[SPORONOX] capsules, solution
[CANESTAN VAGINAL & TOPICAL] cream or inserts
[OXIZOLE] cream, lotion
[MYCIL] cream
Selenium sulfide is often used in shampoos, sold as VERSEL (lotion)
Cl