C151C5 - Antibiotics and Kibdelomycin
The development of antibiotics over the years has not met the growing demand created
by increased resistance and emergence of new pathogens. The first antibiotics were sulfa
drugs in the year 1936, followed by Penicillin in 1941 then came the golden era from
1940 to 1970 where Aminoglycosides, Chloramphenicol, Macrolides, Glycopeptides,
Quinolones, Cephalosporins, Strptogramins, Spectinomycin, Rifampicin,
Clindamycin.(Did what?, This is an imcomplete sentence and I have no idea what you are
trying to convey about these antibiotics, also the list should state what type they are)
After a few decades Carbapenems were discovered in 1985, Streptogramins in 1999,
Oxazolidinones in 2001 and Daptomycin in 2004.(Dates tell me nothing???, what are
they?) Since then there is a sort of drought and lack of funding in the field of antibiotics.
(Why?, statements without reason are useless information)
New antibiotics are very important because of the resurgence of pathogens with
resistance developed due to the evolutionary pressures posed by anti-bacterial agents. Of
these resistant strains, the most famous of which is probably Methicillin-resistant
Staphylococcus aureus (MRSA). These resistant strains are frightening and brilliant in
their adaptively. Medicinal chemists have tried to circumvent the resistance issues by
chemical modifications at the site of known resistance, however the rate of bacterial
resistance is exponentially faster than the rate at which antibiotics can be developed.
Antibiotics are categorized by ; 1) Structural similarities, 2) Mechanism of action
and 3) Target sight.(What are these catagories? Here’s where that list should have gone)
There are various targets that are focus of different classes of antibiotics: cell wall
synthesis inhibitors such as Bacitracin, Daptomycin and Glycopepetides, Metabolism
Inhibitors like Sulfamethoxazole and Trimethoprin, RNA Synthesis inhibitors like
Rifampin, Protein Synthesis inhibitors like Macrolides and Tetracylins and
aminoglycosides such as streptomycin target the A-site of the bacterial ribosomal RNA or
the protein making factory in cells.(Again you give a list of types without describing how
these mechanisms work, where the chemisty???) Aminoglycosides are thought to disrupt
key steps during protein synthesis or translation. Much like the A-site of the ribosomal
RNA, another key step in the life cycle of bacteria is DNA synthesis. Clearly this
pertinent process has been well studies mechanistically and structurally yielding many
potent drugs that target one or multiple steps. Lastly, DNA synthesis is also a drug target.
DNA synthesis like other biological processes is heavily dependent on cofactors,
enzymes and other components that direct, carry out and terminate both essential and
non-essential processes. (First part of paragraph doesn’t tie in with last properly)
One such enzyme called type II isomerase is responsible for the topology of DNA.
DNA replication occurs at 50,000 base pairs per minute and these strands have defects
such as tangles, catenates and crossovers that must be removed. These enzymes catalyze
catenation (linking) and decatenation (unlinking). Gene clusters comprising DNA gyrase
are gyrA and gyrB and these remove supercoils which involves breakage and resealing of
double-strand. Another DNA gyrase is topo IV which removes catenaes (Hermann, 2012).
Two classes of antibiotics – Aminocoumarins and Quinolones target topoisomerases and
disrupt this repair mechanism. These antibiotics inhibit bacterial type II isomerases,
preferentially DNA gyrase and topoisomerase IV (Lodish et al., 2000; Lawson et al.,
2012). Kibdelomycin is the only new novel type II isomerase inhibitor to be discovered
in almost 60 yrs (Demain, 2011). (How do that do it, this would be a great place for a
mechanism and picture explaining how its inhibited.)
Apart from targets in bacterial medicinal chemists also have to take into
consideration the type of organism that is being targeted. There are two types of bacteria:
gram negative like E.coli and gram positive like Staphylococcus aureus. The origins of
the two classes stem from scientist Hans Christian Gram and his observations after
staining bacterium with crystal violet dye. Some of the bacteria become blue whereas
others showed up as red or pink. The retention of the color of the dye earned the blue
batch the label
gram positive bacteria and the bacteria
absent of the original dye color were
labeled gram negative bacteria. This is
not the only distinction between these
classes: gram negative bacteria are harder
to kill because of an selectively
permeable cell wall as shown in the
diagram to the left. Typical antibiotics
which target intercellular processes rarely
work on gram negative because they
cannot properly diffuse into the cell.
Hence antibiotics which target gram
negative bacteria target cell wall
synthesis or somehow bypass this
permeability. Kibdelomycin is one such
antibiotic that has shown activity against
both gram positive and gram negative
bacteria, in other words it kills a broad
range of bacteria. Kibdelomycin was
lated from the forest soil in the Central
African Republic. Some other drugs
similar to Kibdelomycin are
Aminocoumarins, Novobiocin,
(confused here, run-on sentence)known that Kibdelomycin and these forementioned
drugs are similar is that all these all these molecules generated similar profiles when
subjected to the Antisense Induced Strain Sensitivity (AISS) test. The AISS test is used to
determine the mechanism of action (MOA) and molecules with similar MOAs are
generally clustered together.(how is this test performed? Chemistry???)The test consists
of 245 RNA antisense strains including ones engineered to represent essential bacterial
processes such as cell wall biosynthesis, transcription and translation. In other words
genetically modified strands that bear known sites targeted by this class of antibiotics are
created, then reacted with different antibiotics and the reaction is monitored. The data
provided elucidates MOAs. With regulation of gene expression by inducible antisense
RNA, systematic elucidation of mechanism of action of small molecule antibiotics
becomes feasible (Donald et al.).
Structural comparison of Kibdelomycin and classing type II topoisomerase inhibitors
Novobiocin & Clorobiocin
In the case of Kibdelomycin the fitness test predicted the mechanism of action of 1)
known coumarin antibiotic, 2) new coumarin analog or 3) a new structural class with a
mechanism of action similar to novobiocin.(What does that even mean???) Kibdelomycin
fit the third profile and underwent further structural, mechanistic and concentration
studies. Using various NMR techniques including ROESY and COSY fragments of the
molecule were used to compile a complete structural picture.(How?) Kibdelomycin is
structurally very close to aminocoumarin’s which are also a class of DNA gyrase
inhibitors. (Compare these to?)Mechanistic studies showed that Kibdelomycin, similar to
aminocoumarins was specifically targeting ATPase activity of DNA gyrase (gyrA/B) and
topoIV (parC/E). It is clear that Kibdelomycin targets DNA synthesis and replication. It
was also discovered that not only is Kibdelomycin potent against bacteria but it is also
potent against strains that have developed resistance to known antibiotics. The AISS
profiling process is a tool that can be implemented to systematical organizes the search
for new, desperately needed antibacterial candidates.(You already stated this before)
Kibdelomycin itself can potentially become a much awaited solution to the growing
problem of diseases caused by bacteria and bacterial resistance. The AISS profile test will
accelerate the process of the search for new potential drugs.
Additional parameter of determining the potency of drugs is known as IC50 value
or 50% of the inhibitory concentration and minimum inhibitory concentration or the least
amount of drug needed to see activity.(This is false, this is the concentration needed for
50% binding affinity to target site,ICMin is rarely if ever used (Trust me I’m a Med
Chemist)) Kibdelomycin was just as potent as the existing aminocoumarins: In a catalytic
ATPase assay Kibdelomycin inhibited DNA gyrase ATPase at an IC50 value of 11nM and
topoIV ATPase at 900nM.(Again numbers mean nothing without explaining what that
represents on a physical level) In other cases Kibdelomycin showed superior activity: a S.
aureus strain 125 fold resistant to coumermycin A1 (MB 5957/H7) was 4 times less
resistant to Kibdelomycin (Philips et. al). The MIC values of Kibdelomycin when
compared to other DNA gyrase inhibitors attest to its strong antibacterial activity. In
conclusion, an incredibly intelligent screening process has led to the discovery of
Kibdelomycin, a structurally new, mechanistically familiar, fascinating new DNA type II
isomerase inhibitor.
It is very important to mention that these numbers for Kibdelomycin are from invitro assays; that is in buffers and test-tubes not inside biological systems under
physiological conditions. Therefore, although the story of Kibdelomycin is exciting it
remains incomplete. The structural exoticness of the molecule was perhaps one the main
reasons it excited the scientific community. Arrays of molecules have shown promise in
in-vitro testing so the numbers related to do not speak much to the actual potential of the
molecule as a drug because there are numerous obstacles that a molecule has to encounter
before reaching the target. Furthermore, being structurally so similar to existing
antibiotics it is reasonable to expect that Kibdelomycin will most likely encounter similar
resistance, toxicity and other known issues. Nevertheless, this is an good attempt
shedding light on the increasingly urgent need for antibiotics.
Overall this essay was minimally informative. Should have more pictures and diagrams
for references. Also unclear as to the end message the entire essay is trying to convey…
half was about regular antibiotics, half seemed about Kibdelomysin so overall unclear
essay direction. Also should include a story about the discovery and development of
Kibdelomycin, I personally know this was derived from Streptomyces which are Fungilike bacteria found in the ground soil and rainforest then the molecule was further
modified for activity by med chemists. Telling a story about how the most promising
antibiotic in Phase III trials right now came from the dirt can really be impactful I believe.
Also the Medicinal Chemistry used to modify the molecule would blow your mind. Also
in vivo side effects if any would be nice to mention, if there is none this is great news.
Just some thoughts, cheers 
References:
C. et al. Biological Activities of Novel Gyrase Inhibitors of the Aminocoumarin Class.
(2008). Anti. Ag. Chem. (2009). 52, 1982.
Donald, R. et al. A Staphylococcus aureus Fitness Test Platform for Mechanism-Based
Profiling of Antibacterial Compounds. (2009). Chem. Bio. 16, 826-836.
Gram-negative Bacteria vs Gram-positive Bacteria.
http://www.diffen.com/difference/Gramnegative_Bacteria_vs_Gram-positive_Bacteria
Anderle
Hermann, T. Antibiotics Classes & Targets Part III: Drugs Targeting DNA & RNA
Biosynthesis. Chem 259. (2012). Department of Chemistry and Biochemistry, University
of California, San Diego.
Lodish H., Berk A., Zipursky S.L., et al. Molecular Cell Biology. 4th edition. New York:
W. H. Freeman. (2000). The Role of Topoisomerases in DNA Replication.
Philips, J.W. et al., Discovery of Kibdelomycin, A Potent New Class of Bacterial Type II
Topoisomerase Inhibitor by Chemical-Genetic Profiling in Staphylococcus aureus.
(2011). Chem. Bio. 18, 955–965.
Wright, G. D. Making Sense of Antisense in Antibiotic Drug Discovery. Cell Host &
Microbe. 6, 197–198