Infectious diseases are clinically evident illnesses caused by pathogenic biological agents like bacteria, viruses, fungi or protozoa infecting a host organism. Tuberculosis is a global epidemic caused by Mycobacterium tuberculosis, an airborne pathogen. It infects macrophages in the lungs, with two possible outcomes - the macrophage can eradicate the pathogen or the pathogen can multiply, destroying cells and infecting new ones. Most infections are asymptomatic but latent infections can progress to active disease, which if left untreated kills over 50% of infected individuals. The first line drugs used to treat TB include isoniazid and rifampin, discovered in the 1950s. Isoniazid inhibits mycolic acid synthesis while rif

2. INFECTIOUS DISEASES

Infectious
diseases,
also
known
as
contagious
diseases or transmissible diseases, and include communicable
diseases,
comprise
clinically
evident
illness
(i.e.,
characteristic medical signs and/or symptoms of disease)
resulting from the infection, presence and growth
of pathogenic biological agents in an individual host organism.

The pathogen can be a bacteria, virus, fungus or a protozoan

3. TUBERCULOSIS : A GLOBAL EPIDEMIC

Tuberculosis (TB) is an ancient disease that has caused inestimable
suffering and claimed millions of lives over the centuries.

and close to 1.8 million deaths annually

Caused by various strains of mycobacteria usually Mycobacterium
tuberculosis, an airborne pathogen, that infects macrophages in the lungs

Two possible outcomes :

Infected macrophage can be recognized by effectors of immune system and
eradicated

Bacilli may further multiply in the cell leading to its destruction and the infection
of new macrophages drawn to the site of infection. This initiate T cell mediated
adaptive immunity to eradicate the bacilli which if fails then it grows and spread
to extra pulmonary sites.

5. 
Most infections asymptomatic, latent infection

About one in ten latent infections eventually progress to
active disease, which, if left untreated, kills more than 50%
of those infected.

HIV increases the risk of developing a full –borne disease.

7. CELL WALL OF MYCOBACTERIUM TUBERCULOSIS

8. MEDICAL HISTORY OF CURRENT TB CHEMOTHERAPY

TB drugs introduced in 1940’s and 1950’s
Pyrazinamide
Streptomycin
p-aminosalicyclic
acid
Isoniazi
d
Others like
kanamycin,viomycin,cyclose
rine,ethionamide

9. 
TB drugs introduced in 1960’s and 1970’s
Thioacteazon
e
rifampicin
Others like capreomycin,clofazimine
Ethambuto
l

10. CLASSIFICATION
First line
Ethambutol is EMB or E,
isoniazid is INH or H,
pyrazinamide is PZA or Z,
rifampicin is RMP or R,

Streptomycin is no longer considered as a first line
drug by ATS/IDSA/CDC because of high rates of
resistance)

11. Second line



it may be less effective than the first-line drugs (e.g., paminosalicylic acid
it may have toxic side-effects (e.g., cycloserine)
or it may be unavailable in many developing countries (e.g.,
fluoroquinolones)
aminoglycosides: e.g., amikacin (AMK), kanamycin (KM);
polypeptides: e.g., capreomycin, ;
Fluoroquinolones e.g., ciprofloxacin (CIP) ,levofloxacin, moxifl
oxacin (MXF);
thioamides: e.g. ethionamide, prothionamide

12. Third Line
 Other drugs that may be useful, but are not on the WHO list of
SLDs:
 rifabutin
 macrolides: e.g., clarithromycin (CLR);
 linezolid (LZD);
 thioacetazone (T);
 thioridazine;
 arginine;
 vitamin D;
 R207910.
 they are not very effective (e.g., clarithromycin)
 because their efficacy has not been proven (e.g., linezolid,
R207910).
 Rifabutin is effective, but is not included on the WHO list because
for most developing countries, it is impractically expensive.

13. EMERGENCE OF DRUG RESISTANT TB

Combination
resistance
therapy
used
to
limit
development
of

Who developed DOTS

Even then high relapse rates and 1990’s marked a period of
increasingly resistant TB from mono to MDR-TB(resistant to
INH and RIF)

Treatment with second line drugs with unproven efficacy
and use of broad spectrum agents like fluoroquinolones

14. 
Five per cent of all TB cases are now estimated to be MDR

If cases are there which are resistant to first and second line
drugs , then third line agents that are non-WHO approved
are given.

Emergence of XDR-TB .

Now we have TDR-TB for which no chemotherapeutic
options

15. SPECIAL CHALLENGES IN TB DRUG DEVELOPMENT
Why we need improved stategies ?

improved (shorter and simpler, but still affordable) multidrug
regimens for DS-TB to improve adherence and prevent
development of more resistant strains of M. tuberculosis

shorter, more efficacious, less toxic and less expensive regimens
for MDR-TB and XDR-TB

short,simple, easily tolerable and safe regimens for LTBI

TB drugs with minimal interactions with the cytochrome P450
(CYP)enzyme and other metabolic systems

16. PROBLEMS

Problems with rifampicin

Malabsorption : patients with this disease are malnourished and weight
loss is a common symptom

Heterogeneity of TB pathology- differences in clinical manifestation, host
and pathogen physiology

Each lesion a distinct microenvironment

Drug penetration is limited

Drug should not only penetrate cell wall of bacteria but should be able to
reach it ,within the fibrous necrotic lesion harboring the persistent
organisms.

17. DEVELOPMENT OF THE TWO MOST COMMONLY USED
FIRST LINE AGENTS

Rifampicin

Isoniazid

18. RIFAMYCINS

Most effective and widely used

Rifampin was developed in the Dow-Lepetit Research Laboratories(
Milan, Italy) as part of an extensive program of chemical modification of
the rifamycins, the natural metabolites of Nocardia mediterranei.

Developed in 1960 after extensive SAR performed on rifamycin B

Rifamycin B was the least active component of the rifamycin complex
but showed an extremely low level of toxicity and a moderate level of
therapeutic activity in infections in animals

19. 

First compound with ansa structure consisting of an
aromatic nucleus spanned by an aliphatic bridge, therefore,
known as ansamycins
Rifamycin SV is active compound

20. FROM RIFAMYCIN SV TO RIFAMPICIN

Extensive chemical modifications were made



better oral absorption;
more prolonged antibacterial levels in blood;
and greater activity against mycobacterial infections and
infections due to gram-negative bacteria

21. Changes in ansa chain –less
active
Essential
Subsitution or
elimination-less active
Subsitutuion to keto
groups –no effect

22. ACTIVITY REQUIRED

two free hydroxyls in positions C-21 and C-23 on the ansa chain

two polar groups (either free hydroxyl or carbonyl) at positions C-1 and C-8 of
the naphthoquinone nucleus

conformation of the ansa chain that resulted in certain specific geometric
relations among these four functional groups.

23. 



Rifamycin derivatives with substitutions in position C-3 and/or position C-4
di-alkylamino-4-deoxyrifamycins; phenazino- and phenoxazinorifamycins; 3dialkylamino-alkylrifamycins.
Extensive studies on the 3-dialkylaminomethyl derivatives of rifamycin SV.
the hydrazone of 3-formylrifamycin SV with N-amino-N'methylpiperazine, designated rifampicin or rifampin was the most
active and least toxic

24. RIFAMPICIN

25. MECHANISM OF ACTION

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its betasubunit, Rifampicin acts directly on messenger RNA synthesis.

Much of this acid-fast positive bacteria's membrane is mycolic acid complexed
with peptidoglycan, which allows easy movement of the drug into the cell.

cannot stop the elongation of mRNA once binding to the template-strand of DNA has been
initiated.

The Rifampin-RNA polymerase complex is extremely stable and yet experiments have
shown that this is not due to any form of covalent linkage. It is hypothesized that hydrogen
bonds and π-π bond interactions between naphthoquinone and the aromatic amino acids
are the major stabilizers,

It is this last hypothesis that explains the explosion of multi-drug-resistant bacteria:
mutations in the rpoB gene that replace phenylalanine, tryptophan, and tyrosine with nonaromatic amino acids result in poor bonding between rifampicin and the RNA polymerase.

Rifampicin-resistant bacteria produce RNA Polymerases with subtly different β subunit
structures which are not readily inhibited by the drug.

26. SYNTHESIS

wherein rifamycin S is reacted with a 1,3,5-trisubstituted hexahydro-1,3,5triazine in an aprotic dipolar solvent and optionally in the presence of
formaldehyde, the reaction preferably being carried out without modifying the
pH of the medium and preferably in the presence of certain acid substances,
using controlled time and temperature conditions

1-amino-4-methylpiperazine is then added directly to the reaction mixture,
while keeping the pH value in the range of from 5 to 7, and then isolating the
rifampicin formed.

27. INTERACTIONS


Rifampicin is an inducer of many enzymes of the cytochrome P450 family
Other possible interactions which may not be listed include antiretroviral
agents, everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib,
clarithromycin, caspofungin,
ADVERSE EFEECTS



Influenza like symptoms
Hepatotoxicity
Altered liver function

28. ISONIAZID




also known as isonicotinylhydrazine (INH).
discovered in 1912, and later in 1951 it was found to be effective against
tuberculosis by inhibiting its mycolic acid(wax coat).
never used on its own to treat active tuberculosis because resistance
quickly develops.
Isoniazid also has an antidepressant effect, and it was one of the first
antidepressants discovered

29. SAR

Analog of anti-tubercular drug thiacetazone which had limited use because of toxic effects

Phenyl ring was replaced with pyridine ring as nicotinamide had growth inhibitory
isonicotinaldehyde thiosemicarbazone more active


Other intermediates in synthesis were evaluated leading to discovery of INH

Hundreds of derivatives synthesised bt none improved on activity .N acetyl INH inactive

N alkyl derivatives such as iproniazid and hydrazones such as verazide

Invivo metabolite is INH
effect on Mtb.

30. SYNTHESIS
Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine
to give the amide, followed by displacement of ammonia
by hydrazine

31. MECHANISM OF ACTION
activated by a bacterial catalase-peroxidase enzyme that in M.
tuberculosis is called KatG.
INH
Isonictinoyl radical
acyclic isonicotinoyl –NAD(P) adducts
NAD(P
)
Inhibits NADH dependent enoyl
ACP reductase InhA involved
in fatty acid biosynthesis

32. OTHER DRUGS

PYRAZINAMIDE –intracellular acidification following hydrolysis by Mtb
nicotinamidase, inhibition of fatty acid synthesis

CYCLOSERINE-prevents D –alanine incorporation into peptidoglycan by
inhibiting enzyme alanine racemase

CAPREOMYCIN-inhibit protein synthesis by binding at interface of 30S and 50S
subunit of bacterial ribosome

34. ANTIFUNGAL AGENTS

are increasingly common in immunocompromised and other vulnerable
patients.

The use of antifungal drugs, primarily azoles and polyenes, has increased in
parallel.

azoles are fungistatic and vulnerable to resistance, whereas polyenes cause
toxicity

echinocandins, pneumocandins, and improved azoles.

Promising novel agents in preclinical development include several inhibitors of
fungal protein, lipid and cell wall syntheses

35. AZOLES

An azole is a class of five-membered nitrogen heterocyclic ring compounds
containing at least one other non-carbon atom of either nitrogen, sulfur, or
oxygen
ketoconazole
cklotrimazole
fluconazole

36. POLYENES

37. ECHINOCANDINS

38. PNEUMOCANDINS

41. EMERGING TARGETS





Microtubulin inhibitors like griseofulvin
Topoisomerase inhibitors
Phosphnribosylaminoimidazole carboxylase, an enzyme of
them purine pathway
Amino acid analogs to interfere with amino acid synthesis
Proton ATPases and efflux pumps

42. REFERENCES

Third world diseases by Richard Elliot

Foyes’ Medicinal Chemistry

History of the development of azole derivatives . J. A. Maertens ,Clinical Microbiology and
Infection, Volume 10 Supplement 1, 2004

The discovery and development of amphotericin B. James Dutcher ,Dis Chest 1968;54;296-298

Antifungals: mechanism of action and resistance, established and novel drugs . Nafsika H
Georgopapadakou Current Opinion in Microbiology 1998, 1:547-557

History of the Development of Rifampin . P.sensi ,From the Dow-LepetitR esearchL aboratories,
Milan, Italy. Reviews of infectious diseases * vol. 5, supplement 3 * july-august 1983

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