Disease-causing microbes that have become resistant to drug therapy are an increasing public health problem. Tuberculosis, gonorrhea, malaria, and childhood ear infections are just a few of the diseases that have become hard to treat with antibiotic drugs. Part of the problem is that bacteria and other microorganisms that cause infections are remarkably resilient and can develop ways to survive drugs meant to kill or weaken them. This antibiotic resistance is due largely to the increasing use of antibiotics. Smart use of antibiotics is the key to controlling the spread of resistance. It is important to understand that, although they are very useful drugs, antibiotics designed for bacterial infections are not useful for viral infections such as cold, cough, or flu.
Who is at Risk?
Antibiotic resistance can cause significant danger and suffering for children and adults who have common infections, once easily treatable with antibiotics.
Sources: U.S. Food and Drug Administration, Centers for Disease Control and Prevention
Challenging Lethal Bacteria
M. Reza Ghadiri, Ph.D., Professor of Chemistry at TSRI has published a paper in Nature that describes a general nanochemical approach to designing drugs to combat such problems as infections with antibiotic resistant bacteria. Deadly strains of bacteria have become resistant to even the most state-of-the-art drug defenses. Ghadiri and his team of TSRI scientists have created a class of biological materials (or synthetic biomolecules) known as cyclic peptide nanotubes, which stack inside the cell membranes of bacteria, and poke holes in their membranes, killing the cells. These "nanotube" stacks have demonstrated strong bactericidal activity against a number of deadly pathogens including multidrug-resistant Staphylococcus aureus, one of the most common hospital-acquired infections.
Antibiotic-resistant bacteria are a growing public health threat worldwide, and the World Health Organization estimates the total cost of treating all hospital-borne antibiotic-resistant infections is about $10 billion a year. An estimated 14,000 deaths every year are blamed on drug-resistant bacteria common in U.S. hospitals. Ghadiri's creation suggests a welcome new option for doctors and pharmaceutical companies, who are scrambling to find novel ways to kill microbes that are outpacing our ability to design new drugs. Although chemists have long dreamed about making nanobiotics, no one before Ghadiri has come up with a working product.
TSRI Scientists Describe Protein Used by Bacteria and Cancer Cells to Resist Drugs
Scientists at TSRI have solved the structure of a membrane transporter protein called MsbA that is involved in resisting antibiotics and chemotherapy. Assistant Professor Geoffrey Chang, Ph.D., and his colleagues solved the structures using high-resolution x-ray crystallography. The structure reveals molecular details that could be useful for improving cancer therapy and fighting antibiotic-resistant bacteria. In the last few decades, mutant strains of several types of bacteria with the ability to resist antibiotics have emerged, including those that cause TB, pneumonia, cholera, typhoid, salmonella, and staphylococcal dysentery. The bacteria that were once contained by drugs are now outstripping the ability of drugs to contain them, and as a result, many diseases are coming back … resistant to the antibiotics that have been used to treat them.
One way that bacteria resist antibiotic drugs is by using membrane transporters - large proteins that sit in the cell membrane and move other molecules in and out of the cell. MsbA is part of one of the largest superfamilies of transporter molecules. The structure of MsbA may help scientists design compounds to block its action. Coming up with a way to block this transporter would potentially make antibiotics more potent. The solved structure may also lead to ways of improving cancer chemotherapy. Humans have proteins called multidrug resistance transporters that are similar in function to MsbA. In human cells, these transporters play an essential protective role by removing harmful toxins, and transporter proteins are often found in the human gut, colon, urinary tract, and mammary tissue.
Unfortunately, this protective role can reduce the efficacy of certain cancer treatments since the drugs are perceived as toxins. Having a high resolution structure such as the one Chang and his colleagues solved could open the door for scientists to design a new class of drugs that patients would take in conjunction with antibiotic or chemotherapeutic agents to keep those drugs in the cells and increase their efficacy.
Researchers Map A Complex Molecular Assembly "Landscape" For The First Time - Information May Offer New Insights Into Drug Resistance
For the first time, scientists at The Scripps Research Institute have developed a highly detailed kinetic and thermodynamic landscape that describes the mechanisms of macromolecular synthesis, findings that may help spur advances in the global challenges of antibiotic drug resistance. In their study, the researchers showed that assembly of the 30S ribosomal subunit is a "complex dance" in which 20 smaller proteins bind to ribosomal RNA (rRNA) as it folds, allowing it to play a major role in the translation of messenger RNA (mRNA), which encodes and carries information from DNA to protein synthesis sites. The 30S ribosomal subunit is important because it's the molecular target of a number of commonly used antibiotics. Scripps Research Professor James Williamson, Ph.D., led the study. Williamson and his colleagues used a variety of biochemistry tools, including fluorescence, calorimetry, and mass spectrometry to map the assembly of the 30S subunit - when it folds and when proteins bind to it.
The study's use of these imaging methods allows this intercellular landscape to be "seen" for the first time, making it possible to construct an accurate assembly framework for other large macromolecular complexes that could help scientists create new ways to combat the recent emergence of drug resistant strains of bacteria. This new understanding may also offer insights into a number of other biological mysteries including the origin of life and replication of viruses.
Scientists Re-engineer A Well-known Antibiotic To Counter Drug Resistance - New Molecule Could Help In Treating Hospital Infections
Scientists at The Scripps Research Institute have successfully re-engineered a well-known antibiotic to insure its effectiveness against sensitive as well as resistant enterococci, a common strain of bacteria responsible for widespread hospital infections. The scientists replaced a single atom from the molecular structure of vancomycin aglycon, a glycopeptide antibiotic that attacks the bacteria by inhibiting cell wall synthesis, significantly increasing the drug's spectrum of activity. In recent years, a number of the most common strains of enterococci have become resistant to vancomycin and use of the antibiotic has been under scrutiny. This re-engineering effort could help make the drug more effective in treating infections produced by vancomycin resistance enterococci (VRE), a serious and growing problem in the nation's hospitals. While several antibiotics target a bacterium's cell wall, vancomycin binds to a specific component of this wall. Drug resistance results when the VRE actually alters these cell-wall components, interfering with the drug's ability to bind to the bacterium. According to the Centers for Disease Control, VRE were first reported in 1986, nearly 30 years after the introduction of the drug. The study was conducted by Professor Dale L. Boger, Ph.D., of the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology.
The continued rise of vancomycin-resistant infection poses a serious threat to hospital patients in the U.S. and around the world. These infections not only increase the length of hospital stays, but they raise patient mortality rates as well. Boger's successful synthesis of a novel vancomycin analogue with a molecular structure that restores much of the drug's binding ability could potentially lead to the development of a new generation of antibiotics that could prove far more effective against vancomycin-resistant infections than what is available today. The most common strains of VRE - called VanA and VanB - are both capable of inhibiting the antibiotic's ability to bind to the bacteria to such a degree that the loss of antimicrobial activity is reduced nearly 1,000 fold. In the study, the scientists developed two different re-engineered antibiotics and compared them in an antimicrobial assay against VanA, a strain of the bacteria that is highly resistant to treatment by glycopeptide antibiotics, including vancomycin and teicoplanin (a somewhat newer drug similar to vancomycin). Both showed a significant increase in binding ability - roughly 40 times more potent than today's version of the drug. The actual re-engineering was extremely challenging, requiring not only a detailed molecular level understanding of the origin of the vancomycin resistance but a total of 24 sequential chemical steps to prepare the new antibiotics; in this case, a single atom in vancomycin was altered to counter an analogous single atom change in the bacterial cell wall that accounts for the resistance. The results suggest that no matter how the VRE altered the cell wall component, it was still sensitive to treatment by the re-engineered vancomycin analogues. The complex chemical synthesis of the glycopeptide antibiotics was developed with the specific idea that this breakthrough technology could be used to alter and enhance their therapeutic properties. Boger and his colleagues hope that their pioneering efforts will spur further research into the development of more potent antibiotics.
Scientists Demonstrate New Way Of Fighting Antibiotic Resistance
A team of scientists at The Scripps Research Institute and the University of Wisconsin has demonstrated a new way of fighting antibiotic resistance: by stopping evolution. The scientists described how a protein called LexA in the bacterium Escherichia coli promotes mutations and helps the pathogen evolve resistance to antibiotics. The scientists also show that E. coli evolution could be halted in its tracks by subjecting the bacteria to compounds that block LexA. Interfering with this protein renders the bacteria unable to evolve resistance to the common antibiotics ciprofloxacin and rifampicin.
If this pathway is inhibited, the bacteria cannot evolve. Scripps Research Assistant Professor Floyd Romesberg, Ph.D., led the study. Since the evolution of resistance is under the control of LexA, compounds that block the protein might prolong the potency of existing antibiotics.
Scripps Research Team Blocks Bacterial Communication System To Prevent Deadly Staph Infections
In hopes of combating the growing scourge of antibiotic-resistant bacteria, in particular drug-resistant staph bacteria, a team of scientists from The Scripps Research Institute has designed a new type of vaccine that could one day be used in humans to block the onset of infection. The advantage of the new vaccine is that it would work not only on current bacterial resistant stains but also would not induce the potential for new bacterial resistance because, rather than killing bacterial cells, it blocks their communication system, preventing the shift from harmless to virulent, thus allowing the body's natural defenses to combat the bacteria. Staph and other infections are becoming increasingly deadly because many strains of the bacteria that cause disease develop resistance to the array of antibiotics used to control them. A recent Centers for Disease Control (CDC) report estimated that more than 94,000 Americans were infected in 1995 by a drug-resistant staph "superbug" called methicillin-resistant Staphylococcus aureus(MRSA), and more than 18,000 Americans died that year during hospital stays involving this type of infection. The bacterial infection process is dependent on a sort of chemical conversation between individual bacterial cells, referred to as quorum sensing. In their free-living state, bacteria are typically easy to kill and non-virulent. The shift to virulence is dependent on small molecules emitted by bacteria known as autoinducers, because bacteria sense when concentrations of these autoinducers are high enough to suggest a large number of other bacteria are present.
Bacteria basically sense they have enough of their companions around to allow them to feel they're in a favorable environment to start turning on certain genes. Professor Kim Janda, Ph.D., director of the Worm Institute for Research and Medicine at Scripps Research and a vaccine expert who has worked on the development of vaccines for obesity and drugs of addiction, among other problems, led the project. The genes turned on by quorum sensing may encode proteins harmless to their hosts, but they can also code for the toxins and other products arising from bacterial infections that cause disease. Sequestering autoinducers in some way could therefore block quorum sensing and, hence, the establishment of infections. The scientists predict that such a strategy would not lead to resistance in bacteria because it wouldn't kill the cells. Bacteria would simply remain in an inert form because they would be tricked into "thinking" not enough other cells were present to shift into their virulent mode. Bacteria use a variety of genetic mechanisms in quorum sensing. The Scripps Research team focused on Gram-positive bacteria, whose quorum sensing is controlled by four basic types of autoinducers tied to a circuit known as the accessory gene regulator. Based on the known structure of one of these autoinducers, the team designed a molecule known as a hapten that, when conjugated with specific proteins using well-established procedures, induces the production of antibodies by the immune system.