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Microbial
Armageddon: Vancomycin v/s MRSA and VRE
There
is a need to aggressively develop new, more effective drugs that
can overcome bacterial resistance, say Dr Rajesh Kasliwal
and Dr Mahindra Makhija
Vancomycin
is a clinically indispensable antibiotic and is the drug of last
resort for treatment of multidrug-resistant infections. Bacterial
resistance to vancomycin is now emerging. Print and television media
frequently highlight the problems of superbugs; supposedly untreatable
antimicrobial resistant bacterial pathogens. In most cases they
are referring to multi-resistant or methicillin-resistant staphlococcus
aureus (MRSA) and vancomycin resistant enterococci (VRE) which are
usually resistant to all available antimicrobials.
S
aureus is a potentially lethal staph that occurs naturally in humans,
residing on the skin and along the mucous membranes. This opportunistic
microbe typically needs a break in the skin to invade the body.
It can form an abscess at that spot or travel in the bloodstream
to infect kidneys, bones, or other tissues.
The
most frequent infections caused by enterococci are UTIs. The second
most frequent are intra-abdominal and pelvic sepsis and surgical
wound infections, in which enterococci are almost always part of
a mixed flora of colonic organisms. The third most frequent infections
are bacteremias, both primary and secondary. Although enterococcal
endocarditis is relatively rare, it is difficult to treat because
of the relative resistance of enterococci to antimicrobial agents.
Meningitis occurs at even lower frequency but is potentially serious.
Now,
a strain of staphylococcus infecting a four-month-old Japanese boy
has withstood a pharmaceutical onslaught from vancomycin, physicians’
lone remaining surefire drug against the bacterium. S aureus, had
already acquired resistance to every other antibiotic. VREs were
first noticed in England in 1988, in the USA in 1989, and are now
reported almost worldwide. These reports have also sent a shudder
through the research community, which some scientists claim has
become complacent about resistant microbes.
At
worst, the S aureus could signal the rise of a microbe that no drug
on the world market can handle. Acquisition of high-level vancomycin
resistance in MRSA would truly create a ‘superbug’ to
be feared above all others.
Once
a few bacteria become resistant, the resistance factors can become
widespread among pathogens. These are sentinel cases in New York,
Japan, and elsewhere, and we may not heed the warning. We need to
pursue aggressively development of new, more effective drugs that
can overcome bacterial resistance.
Vancomycin
meets its Waterloo
Vancomycin
had been used for 30 years without the emergence of enterococcal
resistance. A possible link with the use of the related antibiotic,
Avoparcin, in the veterinary industry has been suggested and a number
of countries have moved to ban its use. However, it is more likely
that the emergence of VRE relates directly to the heavy usage of
cephalosporins (to which enterococci are totally resistant) and
vancomycin in some hospitals.
The
antibiotic activity of vancomycin involves interference with the
biosynthesis of the bacterial cell wall peptidogylcan by interacting
with the terminal D-alanine-D-alanine group of the peptidoglycan
precursors. There are four recognised VRE phenotypes: VanA, VanB,
VanC and VanD. Each has a characteristic pattern of expression and
associated teicoplanin susceptibility.
VanA
is inducible by vancomycin or teicoplanin and produces resistance
to both. The VanA gene produces precursors which terminate in D-alanine-D-lactate,
thus preventing vancomycin binding.
The
mechanism of resistance is similar for the VanB phenotype, which
is associated predominately with E.faecium. It is inducible by vancomycin
only but exposure to vancomycin also leads to teicoplanin resistance.
The
VanC phenotype has a similar, but different, mechanism. Resistance
is constitutive and is caused by chromosomally encoded genes fund
in all strains of E.cassiloflavis, E.flaescens and E.gallinarum,
species which are rarely isolated from patients. These genes produce
relatively low levels of vancomycin resistance without teicoplanin
resistance and are not transferable.
VanD
is similar to VanB but has been noted only in a rare strain of E.faecium.
Bacteria
are able to swap drug-resistance genes among species — in fact,
the vancomycin-resistant Staphylococcus aureus may have garnered
its capability from another, less virulent microbe called enterococcus.
Recent reports indicate that instead of swapping genes, S aureus
has apparently become resistant by mutating its own genes. Exactly
how S aureus did so remains unknown.
A
quiver short of arrows
It
is difficult to generate enthusiasm in funding agencies or industry
for proactive drug research. Even though we can be quite certain
that the vancomycin resistance problem will get much worse rather
than go away, adequate funding to solve the problem will probably
not materialize until it is more generally perceived as an immediate
and broad threat to public health.
Despite
a recent research push almost worldwide, the pharmaceutical industry
could be caught flat-footed. Work on new antibiotics slowed in the
1980s and early 1990s. It can take a decade to bring a new antibiotic
to market.
Synercid
was introduced by Aventis in 1999. It is a mixture of two streptogramins,
quinpristin and dalfopristin, and is effective against E faecium
but not E faecalis.
Linezolid
(Zyvox, Pharmacia), the first of the oxazolidone class of antibiotics
on the market, is active against both E.faecalis and E faecium.
It was FDA approved in April 2000 for the treatment of E faecium
infections and of pneumonia and skin and skin structures infections.
Resistance has already been reported.
Chemistry:
A ray of hope
Nicolaou’s
team has used chemistry answer to biology’s random mutation:
combinatorial synthesis. This involves making a vast library of
different candidate molecules for a particular function, such as
drug action, and then screening the library for those that work.
Combinatorial synthesis is widely used by the pharmaceutical industry
for drug development.
But
they did not search blindly. Knowing that vancomycin is a good antibiotic,
they looked for closely related molecules that might improve on
it. In particular, it’s known that vancomycin molecules perform
better in pairs than alone.
The
antibiotic works by sticking to molecules that bacteria make while
building their cell walls. By stopping the synthesis of these proteins,
vancomycin prevents the bacterial cells from multiplying. When the
antibiotic molecules stick to one another back to back, they can
bind to their targets even more efficiently.
So
Nicolaou’s group reasoned that two vancomycins permanently
linked together might make a better antibiotic. They used a combinatorial
approach to identify the best tether, rifling through a library
of different lengths and different molecular constituents.
Crucially,
they conducted these searches after forming the various pairs in
the presence of the cell proteins to which they must bind for the
antibiotic to work. This ensured that they found the best vancomycin
analogues and linking units for the task at hand.
Software
& brainware to develop chemical arsenal
In
the past few years, an enormous expansion in the computational arsenals
of academic and industrial research has transformed scientific discovery
like never before. Driven by advances in CPU and software performance,
improved scalability, and algorithms that make more efficient use
of parallel computing, powerful scientific simulations and modelling
are bringing revolutionary insights to a wide array of disciplines.
Loll
and Axelsen were the first to describe the structure of vancomycin.
Using the detailed structural information provided by their studies,
the scientists have used powerful computational chemistry techniques
to design ancomycin variants that might be able to circumvent bacterial
resistance.
At
the State University of New York at Buffalo (UB), Dr Russ Miller
is refining new techniques for molecular structure determination
using a 64-processor Origin2000 server. Aided by a novel computational
method called Shake-and-Bake (SnB), Miller is solving larger and
more complex molecular structures than was previously possible.
This is the kind of computational power that will lead to the development
of more effective drugs.
In
a key study, Miller is looking at modifications in the structure
of vancomycin, the antibiotic of last resort for many infections.
If the structure of the antibiotic is understood, then it can be
modified. Specifically, better knowledge of the structure allows
researchers to understand vancomycin’s mechanical and chemical
interactions with the bacteria it targets. In turn, that knowledge
aids in modifying the antibiotic’s structure to ensure that
it will continue to recognize and bind with its target proteins.
Lessons
to be learnt
Apathy
is a glove in which evil slips his hands, and before this evil of
MRSA and VRE slips its hands due to the apathetic nature of our
pharmaceutical industry towards this public health menace, we need
to develop new strategies for combating infections that occur in
patients after surgery. Given the fast-paced global spread of the
MRSA and VRE, coupled with indiscriminate use of powerful antibiotics
like vancomycin, soon there will be a time when will be fighting
a losing battle.
The
writers Dr Rajesh Kasliwal and Dr Mahindra Makhija are with Neon
Antibiotics, Dahisar, Mumbai
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