PDF assignment

1. February 2, 2017

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Sr.
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Topic description Pg.
1 Antibiotics 3
2 Antifungal drugs 8
3 Antiviral drugs 10
4 References 12

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Different types of drugs are now in use to treat infections caused by microbes including
bacteria, fungi and viruses. Recently discovered agents to treat most of the contagions are the
topic of this assignment
A) Antibiotics
“Antibiotics are the substances produced by a microbe to selectively kill
another microbe or to inhibit the growth of it.”
Antibiotics are mostly secreted by bacteria and fungi and are used to kill bacteria to overcome
infectious diseases. These chemical substances are usually non-toxic to the host organism.
History
The discovery of the first antibiotic penicillin in the 1928 by Sir Alexander Fleming, made a
big impact on human history. This
discovery was then followed by
sulfa drugs which were
discovered by Gerhard Domagk
in 1935. After these, a number of
antibiotic agents including
chloramphenicol, tetracycline,
and macrolides were discovered
in 1950 (Figure 1). Until now, a
large number of antibiotics have
been discovered and also
synthetic antibiotics are being
manufactured. These synthetic
antibiotics, which are usually
chemically related to natural
antibiotics, have since been
produced that accomplish comparable tasks.
The discoveries of such novel antibiotics not only did lead to a cure for bacterial infections that
were once deadly, but it also led a big interest in finding new antibiotics.
Today many different types of antibiotics are available, and they fight infection in several ways
by adopting various mechanisms.
Figure 1: History of Antibiotics

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Latest discoveries
Most of the newly discovered antibiotics belong to following classes:
a) Super gram positive antibiotics
b) Super gram negative antibiotics
c) Antibiotics with anaerobe coverage
d) Teixobactin
These newly discovered antibiotics act by adopting different mechanisms (Figure 4) to kill the
pathogenic microbe. Their details and mode of actions are described below:
a) Super gram positive antibiotics
These antibiotics are the drugs which have strong activity against methicillin resistant
Staphylococcus aureus (MRSA), Streptococci, and Enterococcus species.
Examples:
i) Vanomycin, Dalbavancin
Mechanism of action:
The glycopeptide in these drugs, acts to inhibit the synthesis and growth of Gram positive
bacteria by preventing the –D-Ala-D-Ala linkage formation (Figure 2).
Uses:
This antibiotic is used to treat meningitis and skin infections.
Figure 2: Vanomycin in action

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ii) Linezolid
Mechanism of action:
It is a bacteriostatic antibiotic which act to inhibit the growth of pathogen by blocking the 50S
ribosome to prevent the protein synthesis.
Uses:
This drug is prescribed to treat skin and soft tissue infections.
iii) Daptomycin
Mechanism of action:
It is a strong bactericidal agent and lipopeptide antibiotic which forms transmembrane channels
and depolarizes the bacterial cells to cause damage to pathogenic microbes.
Uses:
It is recommended to use for complicated skin/soft tissue infections.
b) Super gram negative antibiotics
These antibiotics act against Pseudomonas species. Pseudomonas aeruginosa is a non-
fermenting Gram-negative bacillus that inhabits a variety of environments (soil, water) and
causes nosocomial infections (HAP/VAP, catheter-related infections, UTIs, post-surgical) and
commonly affects immunocompromised patients (common cause of neutropenic fever,
ecthyma gangrenosum), cystic fibrosis, and burn patients. It is feared due both for its inherent
resistance to most antibiotics as well as its propensity to develop resistance.
Examples:
i) Polymyxins
Mechanism of action:
This act as cationic detergent that binds to (and disrupts) lipids of bacterial cell
membranes. Moreover, these act as a strong bactericidal agents.
Uses:
These are generally reserved for multidrug-resistant and gram negative infections due to
bacteria which cause pneumonia, bacteremia, and others.

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c) Antibiotics with anaerobe coverage
Infections in which anaerobes are likely to play an important role include CNS abscesses,
infections arising from the oral cavity and major pathogens include Peptostreptococcus,
microaerophilic streptococci, Fusobacterium, and others.
Examples:
i) Metronidazole
Mechanism of action:
The antibiotic is selectively taken up by anaerobic bacteria and is then reduced by proteins in
the electron transport chain ultimately leading to DNA disruption.
Uses:
It can be used for treating anaerobic infections usually in conjunction with other agents (since
anaerobes usually part of a polymicrobial infection). Also used for mild-moderate protozoal
infections.
d) Teixobactin
For this drug, it is evident from the experiments that it could be effective for decades to cure
bacterial infections which became impossible to treat due to resistance strain development.
Mechanism of action:
This drug work so effectively due to its ability to destroy pathogens by causing their cell walls
to break down. Most antibiotics target
bacteria’s proteins and genes, which can
allow the bacteria to mutate and develop
resistance to the attack (Figure 3).
Uses:
Teixobactin targets many drug-resistant
bacteria, including those that cause the
“superbug” Streptococcus and the bacteria
that causes infective endocarditis.
Teixobactin is also effective against
tuberculosis, which now has multiple
resistant strains to all available antibiotics. Figure 3: Teixobactin in action

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A) B)
C) D)
Figure 4: A) Antibiotic production on bacterial cell surface
Action of antibiotic on B) bacterial cell wall, C) bacterial DNA, D) bacterial ribosome

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B) Antifungal drugs
An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with
minimal toxicity to the host. Antifungal medicines are used to treat fungal infections, which
are most commonly found on the skin, hair and nails. Some of the fungal drugs with their
mechanisms are given below (Figure 5).
a) AZOLES
Azoles are the antifungal drugs which inhibit ergosterol synthesis which is an important
component of fungal cell membranes.
Examples:
i) Fluconazole
It is a drug of choice for non-severe Candida infections, including Candida albicans, EXCEPT
Candida glabrata and C.krusei. It is used for Cryptococcus infections (maintenance phase for
cryptococcal meningitis after induction with Ampho B), Coccidioidomycosis, Histoplasmosis
(but inferior to Itraconazole), and others.
ii) Itraconazole
It has best activity among azoles vs Histoplasmosis and used for non-severe cases, and can also
follow induction phase with Ambisome for severe disease. It is also used for Blastomycosis,
sometimes Cocci and Paracocci infections. Moreover, commonly used for prophylaxis in
transplant patients.
iii) Voriconazole
It acts as fungicidal for many molds and is a drug of choice for Invasive Aspergillosis. It is
more active as compared to Fusarium and Scedosporium. It also works against most Candida
species.
iv) Posaconazole
It has a broad spectrum of activity against yeast (including many Fluconazole-resistant
Candida), molds, and endemic fungi. It is used as 2nd-line therapy for many severe fungal
infections, and for fungal prophylaxis in high-risk patients (e.g bone marrow recipients).

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v) Isavuconazole
This is the newest triazole which is currently undergoing Phase III trials. It possesses broad
activity against all fungi (like Posaconazole) including Candida, Aspergillus, Mucormycosis,
Fusarium, Scedosporium, and Cryptococcus.
b) Echinocandins
It prevents fungi by inhibiting the glucan synthesis in fungal cell wall by blocking beta 1,3 D-
glucan synthase a fungicidal agent. All Echinocandins lack the activity vs Cryptococcus,
Zygomycetes, and Fusarium.
c) Flutycosine
Its mechanism involves 5-FC interferes with DNA and protein synthesis. It is preferably used
in combination with Amphoterecin B for initial management of several severe fungal infections
such as severe cryptococcal pneumonia and meningitis, severe candidal infections
(endocarditis, meningitis).
d) Polyene antifungal drugs
Amphotericin, nystatin, and pimaricin interact with sterols in the cell membrane (ergosterol
in fungi, cholesterol in humans) to form channels through which small molecules leak from
the inside of the fungal cell to the outside.
Figure 5: Targets for antifungal drugs

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C) Antiviral drugs
For over 60 years, the use of microbially-produced or semi-synthetic antibiotics has helped to
cure life-threatening bacterial diseases in many millions of people. The development of drugs
to effectively combat viral diseases, however, has proven to be much more difficult. Most viral
diseases, with the exception of those caused by human immunodeficiency virus, are self-
limited illnesses that do not require specific antiviral therapy.
The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and
influenza viruses. Some antiviral drugs possess multiple potential clinical applications and used
on large scale to treat viral infections.
Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major
mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes
that encode for the viral kinases required for the activation of certain drugs such as ganciclovir.
Widespread antiviral resistance has limited the clinical applications of antiviral drugs for the
prevention and treatment of various viral infections.
Advances in understanding the detailed molecular biology of virus replication cycles, coupled
with determination of detailed three dimensional structures of viral molecules, are now making
possible the development of highly specific and effective anti-viral drugs. Examples along with
their mechanism of action are describes here (Figure 6):
a) Amantadine and Rimantadine
These drugs act as the inhibitor for M2 channel inhibitors.
Mechanism of action
At high concentrations, amantadine and rimantadine non-specifically raise the pH within
cellular endosomes, thus inhibiting or retarding the acid-induced conformational change in the
viral HA. However, the required concentrations of the drugs are not generally attained in vivo.
At low, pharmacologically relevant concentrations, amantadine and rimantadine specifically
inhibit the ion channel activity of the M2 protein, probably through direct binding to the pore
region of the protein. In doing so, the drugs inhibit acidification of the interior of susceptible
viruses causing its dissociation.
b) Zanamivir and Oseltamivir
These work as neuraminidase inhibitors and prevent viral replication within host.

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Mechanism of action:
Some viruses possess neuraminidase on their outer surface, an enzyme essential for release of
virus particles from infected cells, for prevention of formation of viral aggregates and for viral
spread within the respiratory tract. Neuraminidase cleaves the receptor for influenza viruses,
sialic acid, from glycoproteins and glycolipids. Zanamivir and oseltamivir are analogues of
sialic acid. These compounds specifically inhibit neuraminidase and result in disease
prevention.
Figure 6: Mechanism of action of antiviral drugs
With the advent of the antibiotics, antifungal and antiviral chemical agents, previously fatal
infections can now be treated. However, as modern medicine continues to extend life through
aggressive therapy of other life-threatening diseases such as cancer, there is an increasing
population at risk for opportunistic microbial infections. Such patients represent a special
challenge because they often are left with little host immune function. Therefore,
chemotherapeutic agents should be microbe-cidal and not just microbe-static. The search
continues for therapeutic agents that are nontoxic to the host. Research is also directed toward
immunomodulating agents that can reverse the defects of native host immunity.
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References:
1. Murray, Patrick R, Ken S. Rosenthal, and Michael A. Pfaller. Medical Microbiology.
Philadelphia: Elsevier Mosby, 2005.
2. Coates, A. R., et al. (2011). "Novel classes of antibiotics or more of the same?" Br J
Pharmacol 163(1): 184-194.
3. Ling, L. L., et al. (2015). "A new antibiotic kills pathogens without detectable
resistance." Nature 517(7535): 455-459.
4. Ventola, C. L. (2015). "The Antibiotic Resistance Crisis: Part 1: Causes and Threats."
P t 40(4): 277-283.
5. Razonable RR. Antiviral Drugs for viruses Other than Human Immunodeficiency
Virus, Mayo clinic proceedings. 2011;86(10):1009-
1026.doi:10.4065/mcp.2011.0309
6. The treatment of influenza with antiviral drugs” – Reprinted from CMAJ 07-Jan-03;
168(1): 49–57
7.
8. https://www.cdc.gov/flu/professionals/antivirals/
9. https://www.sciencedaily.com/terms/antiviral_drug.htm
10. http://www.lehigh.edu/~jas0/V14.htmlhttp://www.rapidreferenceinfluenza.com/chapt
er/B978-0-7234-3433-7.50014-1/aim/mechanisms-of-action-of-antivirals