News Release

[Guest guest]

Drug Week

                                                              February

14, 2003

HEADLINE: BACTERIOLOGY: New drug lead fights bacteria that disrupt

quorum

 sensing and biofilms

   University at Buffalo scientists have discovered a promising

new drug lead

 that works by inhibiting the sophisticated bacterial communication

system called

 quorum sensing.

   The new compound is active against Pseudomonas aeruginosa, the

gram-negative

 infection that strikes - and usually kills - cystic fibrosis patients

and many

 others whose immune systems are compromised. The bacteria, like many

others that

 have been routinely treated by antibiotics, have developed strains

that are

 antibiotic-resistant.

   The compound and the method the UB scientists used to develop

it are

 described in the January 25, 2003, issue of Chemistry & Biology.

   A patent application has been filed on the method of synthesis

and the

 compound.

    " With this work, we have taken a critical step toward

inhibiting quorum

 sensing for clinical applications, " said Hiroaki Suga, PhD, UB

associate

 professor of chemistry and corresponding author on the paper.

   Quorum sensing is the process by which bacterial cells " sense "

that their

 numbers have reached a certain level, Suga explained, so that they

then can

 mount an effective attack. The process gets switched on, he said, in

response to

 the autoinducers that accumulate in bacterial cells as they begin

reproducing.

   Once the cells " sense " that a quorum has been reached, they

begin to

 communicate, a process that in turn " throws the switch " for

manufacturing

 virulence factors, such as biofilms.

   These tough, layered, polysaccharide shells provide the

bacteria with a

 nearly impenetrable, self-protective mechanism that makes it

extremely

 difficult, and in some cases impossible, to fight with antibiotics.

    " Underneath the protective biofilm, the cells are happily

reproducing,

 damaging the tissue and producing toxins, " said Suga.

   Based on the structure of the quorum-sensing molecule, the

autoinducer, the

 UB team synthesized a library of compounds. This approach then

allowed the

 scientists to discover a subset of molecules that, like the natural

autoinducer,

 activate quorum sensing.

    " We then synthesized a small, focused library of quorum-sensing

agonists, "

 said Suga. " Surprisingly, this focused library yielded a

quorum-sensing

 antagonist. "

    " It has been shown that knockout of the quorum-sensing genes in

P. aeruginosa

 significantly reduced its virulence, so this cell-to-cell

communication process

 is an interesting new drug target, " he said.

   By disrupting the communication process, he explained, the new

compound could

 lead to drugs that will prevent the formation of biofilms, restoring

the potency

 of antibiotic treatments and limiting the development of antibiotic

resistance.

   Since many other bacterial infections operate through quorum

sensing, this

 molecule likely will boost research into methods to disrupt those as

well, he

 added.

   In addition, he said, compounds that inhibit quorum-sensing

function

 differently from traditional antibiotics by attenuating

pathogenicity, and

 therefore could prove very effective against resistant strains.

   Suga explained that the quorum-sensing system is responsible

for regulating a

 number of genes, including those that control the production of

virulence

 factors.

    " We now have a synthetic molecule that inhibits the master

regulatory gene of

 quorum sensing, " he said.

   While Pseudomonas aeruginosa, which is ubiquitous in hospitals,

has no effect

 on healthy people, it can be lethal to patients whose immune systems

are

 compromised. In addition to cystic fibrosis patients, whose lungs

become clogged

 with the bacteria, it infects patients receiving chemotherapy, burn

patients,

 AIDS patients, those on ventilators, with catheters and others.

    " The resistance problem demands development of a new type of

drug, which

 differs in concept from traditional antibiotics, " said Suga.

    " Our work demonstrates a new strategy for identifying and

designing

 antagonists to quorum sensing, " he said. " We hope that additional

studies in

 this direction lead us to discover even more potent quorum-sensing

antagonists,

 thus generating a new type of antibiotic drug. "

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Becki

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