ANTI-BACTERIAL Compounds
Germicide / antiseptic on skin & disinfectant on things
External use – most are oxidants:
Cl2, O3, I2, NaOCl, H2O2, KMnO4, Chloramine-T
Chloramine-T Phenol(s) Triclosan Methyl salicylate
Phenols: generally toxic through skin but <1.5 % is tolerable
egs. Lysol (= p-cresol), TCP (= trichlorophenol), phenol (carbolic acid, R=H), TriclosanListerine contains menthol, thymol, methyl salicylate and eucalyptol
CH3 SO2 NCl
NaHO R O
OH
Cl
Cl
Cl
OHCOOMe
Quaternary Ammonium Compounds - Mouthwash - R4N+ X-
N (CH2)15CH3
+Br -
OCH2CH2N
CH3
(CH2)11CH3
CH3
+Br
-
Cetyl pyridinium bromide Domiphen bromide(Life, Safeway brands, etc.)
Cetrimonium bromideis (CH3)3N+(CH2)15CH3 Br-
= cetrimide
NH
NH
NH
NH(CH2)6
NH
NH
NH
NH
NH NH
ClCl
Chlorhexidine –for gingivitis
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 stainegs. Streptococcus, Staphylococcus, Pneumonococcus
Game –ve have thin walls with inner and outer membranes and do NOT retain the stainegs. 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 bacteriumTB 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
N
OH N
O
Br
R207910
THE SULFA DRUGS: effective against most Gram +ve, some Gram –ve
FOLIC ACID PABA p-aminobenzoic acid
N
N
N
N
NH
H2N
OH
CONH CHCH2CH2COOH
COOH
H2N COOH
We eat folic acid; bacteria make it from PABA: we can fool them using sulfanilamide so they die of vitamin deficiency
H2N SO2NHRN
N
N S
NR =
a sulfanilamide Sulfapyridine Sulfadiazine Sulfathiazole
H2N SO2NHO
N
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 chrysogenumfound on a cantaloupe in Peoria, Illinois in 1943 gave better yields and is used to make Pen-G
N
S
O
RCONH
COOH
Pen-G has R- = CH2 Pen
OCH2-Pen H2N PenO N
Pen
CH3Cl
H2N Pen
OH
Penicillins: general formula includes the -lactam ring
Pen-V Ampicillin Amoxicillin Cloxacillin
You can make those other than Pen-G by feeding the mould the appropriate acid, RCOOH
Pen-G
Pen-G has to be injected: 600-2400 mg/day IV in 3-4 dosesUseful 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:
-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 -lactam ring and allows normal wall formation: resistant
PenOEt
R=
nafcillin
MeO OMePen
methicillin
Five Penicillins are more resistant to Penicillinase: mainly reserved for Staph infections (egs. Nafcillin and Methicillin)
CEPHALOSPORINS: from mould found in sewage (Sardinia 1950’s)
H2N Ceph
N
S
Z
COOHO
R-CONH
Z=Cl
NCeph
+
N
SH2N
CephN
OCH3
Z =
R = R =
internal -COO-
a cephalosporin Cefachlor (Ceclor) Cefepime (Maxipime)
250 mg/8h, 2g/day max 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 Cef-
Not 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 synthesisToo toxic for use, then last resort for TB
Also from soil: the tetracyclines:
OH O OH O
CONH2
OH
N(CH3)2ZOHX
OH
Chlorotetracycline (Aureomycin)X=Cl, Z=OH
tetra-cyclo = 4 rings Tetracycline (Terramycin, (A,B,C,D) Ambramycin,.....)
X=H, Z=OH
More common ones now:OH O OH O
CONH2
OH
N(CH3)2ZOHX
OH
Doxycycline (Vibramycin) X=H, Z=OH, no OH in ring BMinocycline (Klinomycin) X=NMe2, Z=H, no OH or Me in ring BDemeclocycline (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 skinreduced 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)
HOOH
O
O
O
O
OOH
OMe
OHO NMe2
N NH
HO
Cl
OH
OH
SMe
O
Very widely used More toxic allergic reactions rare 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)
DAPTOMYCIN
NHNH
O
O
NH
NH
O
O
O
O
NH2
O
NHHOOC
NH
HOOC
NHO
O
HN
HN
O
NHO
O
HOOC
NH
H2NO
O
NH
O
NH
HN
(CH2)8CH3
NH2
HOOC
HO
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)
N N N
NH
F
O
HO2C
Related: Norfloxacin (Noroxin)Et in place of cyclopropyl
Some newer ones:
N N
HOOC F
N CH2NH2.HO3SMe
NOMe
O
N
HOOC F
N
O
NO
N
HOOC F
N
O
NH
F
F
Levofloxacin Trovafloxacin Gemifloxacin LEVAQUIN TROVAN
wide use for TB
Others: moxifloxacin; gatifloxacin; ofloxacinTrovan (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 N N
F
O
O
NHCOCH3N
O
F COOH
H2N
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
N-C-O
S
O
OMe
MeO
Cl
O OMe
O
Tolnaftate, Tinactin, Pitrex Fungistop, Triactintopical only, inhibits steroid biosynthesis
Griseofulvin (Fulvicin, Grisovin, Grisactin) hair and nail infections
orally for ‘ringworm’
made by mould penicillin griseofulvin: disrupts the microtubules
Not if pregnant: teratogenNot with alcohol: 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
NN CH2 CH OCH2 Cl
Cl
Cl
Cl
OTHER ANTIFUNGALSTerbinafine [LAMISIL]Ketoconazole [NIZORAL] cream, shampoo, tabletsFluconazole [DIFLUCAN] capsulesItraconazole [SPORONOX] capsules, solutionClotrimazole [CANESTAN VAGINAL & TOPICAL] cream or insertsOxiconazole [OXIZOLE] cream, lotionChlorphenesin [MYCIL] cream
Selenium sulfide is often used in shampoos, sold as VERSEL (lotion)
N
terbinafine(an allylamine)
NNO
O
O
ON
Cl Cl
N
ketoconazole
OH
N
NF
F
N
N
N
N
Fluconazole
NN O
O
ON
Cl Cl
N
N
NN
N
O
Itraconazole
NN
Cl
Clotrimazole
Cl
Cl
N
N
Cl
Cl
Oxiconazole
Cl
O
OH
OH
Chlorphensin
H2NSO2
Cl
COOH
NHO
furosemide