Pharmaceuticals & Vitamin D : Antibacterials


Inhibiting Quorum Sensing in Staphylococcus Epidermidis, a Health Care Pathogen

UW–Madison researchers have synthesized a set of potent peptidic modulators of Staphylococcus epidermidis quorum sensing. Targeting the AgrC receptor, these compounds include the first universal QS inhibitors active against all known groups of S. epidermidis. Others are strongly group- or species-selective and could be applied to selectively modulate either S. epidermidis or S. aureus quorum sensing.

New and More Potent UGM Inhibitors for Treating Tuberculosis, Other Microbial Infections

UW–Madison researchers have developed a new set of UGM inhibitors to fight tuberculosis and other diseases caused by microbial infections. The compounds feature an N-acylsulfonamide motif and are more potent in vitro than inhibitors previously identified by the researchers.

Compound Combination Targets Bacterial Virulence

The researchers have discovered that two lead compounds (E22/M64) can be combined to target multiple QS pathways at the same time (Rhl/Pqs), resulting in enhanced activity against P. aeruginosa and potentially other pathogens. This new cocktail approach is superior because it attenuates virulence factor production across a range of relevant environments where single compounds fail.

Nylon-3 Polymers Active Against Clostridium Difficile

UW–Madison researchers and collaborators at Emory Medical School have developed nylon-3 polymers and copolymers active against C. difficile. The polymers have been shown to inhibit outgrowth/growth of the bacteria in spore and vegetative form.

Natural Antibiotic to Treat Clostridium Infection and More

UW–Madison researchers have identified a potential new antibiotic to treat infections caused by C. difficile, Staphylococcus and other drug-resistant strains. The compound is a natural product called ecteinamycin. It was discovered and isolated from a sea squirt bacterium (Actinomadura). Preliminary data suggests ecteinamycin is potent, selective and able to protect cells against bacterial toxins.

New Broad-Spectrum Antibiotics

A UW–Madison researcher and collaborators have identified an antibiotic compound effective against many drug-resistant, Gram-negative and Gram-positive bacteria. The compound (5-nonyloxytryptamine) and its analogs are small molecule inhibitors that interfere with the bacterial membrane and prevent replication.

The compound has been reported as an anticancer drug but was not previously shown to have antimicrobial properties. It was identified by searching for compounds that cause E. coli bacteria to lack a copy of the chromosome following cell division.

More Potent UGM Inhibitors for Treating Tuberculosis and Other Microbial Infections

UW–Madison researchers and collaborators have identified a potent set of UGM inhibitors that may help fight tuberculosis and other diseases caused by microbial infections. The compounds contain a bicyclic triazolo thiadiazine core with diversified aromatic substituents. They were identified by virtually screening a database of nearly five million commercially available compounds.

The molecules inhibit the growth of microorganisms that depend on UGM to incorporate Galf residues. They also diminish the virulence of pathogenic microorganisms, such as M. tuberculosis, M. smegmatis and Klebsiella pneumonia, that rely on UGM.

Treating Staph Infections, Toxic Shock Syndrome by Disrupting Bacteria Quorum Sensing

UW–Madison researchers have synthesized new peptide-based compounds that can strongly inhibit or activate the AgrC receptors of Staphylococcus.

The compounds are structural variants of the AIP-III cyclic peptide that are produced naturally by the bacteria. The compounds interfere with quorum sensing by inhibiting the AgrC receptor. S. aureus strains can be categorized into four groups depending on the different AgrC receptor that they possess; these different groups are found in different infection types.

Several of the new cyclic peptides are capable of inhibiting all four of the known AgrC receptors, and thereby represent pan-active quorum sensing inhibitors in all groups of staph. Antibiotics may be combined with the compounds to further augment their ability to help treat infections.

A Novel Series of Antimicrobials Target Bacteria Membranes to Overcome Antibiotic Resistance

UW–Madison researchers have developed a novel series of antimicrobial compounds that target the membranes of Gram-positive and Gram-negative bacteria, and are effective both against actively growing and stationary bacteria.

The series of compounds are analogs and derivatives of DCAP, or (2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol).

This series of compounds disrupts the bacterial cell envelope and causes cell death, and has only minor effects on eukaryotic cells. With this discovery, new antimicrobials based on DCAP analogs and derivatives could be used to combat resistant bacterial cells.

Combatting Biofilms by Disrupting Bacteria Quorum Sensing

UW–Madison researchers have developed a set of 2-aminobenzimidazole (2-ABI) derivatives that can almost totally inhibit or disperse biofilms by disrupting QS in Gram-negative bacteria, particularly P. aeruginosa. These small molecules have previously been shown to fight Gram-positive biofilm growth.

The compounds can be developed using known methods and applied in many forms, such as anti-biofilm coatings, hydrogels, disinfectants and pharmaceutical compositions. They work by acting as replacements for naturally occurring QS ligands in the ligand-protein binding system of bacteria. In this way, the compounds disturb coordination signals and thereby impede biofilm formation.

Compound to Treat Staphylococcus aureus Infections Including MRSA Strains

A collaborative research team from the UW System has identified a new antimicrobial compound and several derivatives that have broad spectrum activity against several clinically important gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA), among others.

Initial testing has uncovered the following:
  • Preliminary in vitro studies demonstrate the unformulated compound was efficacious against a number of strains of S. aureus, including MRSA strains.
  • Preliminary in vivo studies demonstrate unformulated compound is both efficacious and safe when administered intraperitoneally (IP) to mice to treat thigh abscess MRSA infections.
  • Compound formulation has been optimized for bioavailability
  • Preliminary safety/toxicity of formulated compound was tested in mice, and the compound was found to be safe for testing in mammals.
  • Preliminary PK studies demonstrate bioavailability is 8 percent with a half-life of 20-30 minutes.
  • Radiolabeled macromolecule synthesis studies have shown the mechanism of action for the drug is not tied to DNA, RNA, or protein synthesis.
Taken together, these results suggest the compound may be a safe, viable, and effective treatment for clinically significant gram-positive infections in humans, including high priority drug resistant strains.

Novel Antibacterial Agents That Modulate Quorum Sensing and Are Effective at Physiological pH

UW-Madison researchers have developed a set of novel agents that modulate quorum sensing but are not hydrolyzed readily at physiological pH.  These compounds are mimics of the native quorum sensing signals used by Gram-negative bacteria, called N-acylated L-homoerine lactones (AHLs).  Non-hydrolysable heterocycles were used to replace the lactone head groups of the AHLs.

Method for Modulating Microbial Quorum Sensing

UW-Madison researchers have developed methods and compounds that reduce virulence by stimulating or disrupting the quorum sensing pathway in bacteria such as Pseudomonas aeruginosa. The compounds have been tested in culture-grown bacteria, but still require animal testing. They probably modulate the quorum sensing pathway by binding to the regulatory protein that is responsive to the authentic quorum sensing inducers. When the pathway is blocked, the bacteria are less virulent and may remain more susceptible to antibiotics because they cannot produce biofilms. If the pathway is stimulated, the bacteria may become prematurely virulent, and the host immune response might be activated before the bacteria can reach high concentrations.

Novel Antibacterial Small Molecules

UW-Madison researchers have developed a versatile platform for screening compounds for antibacterial activity, along with new antibacterial agents that are effective against Gram-positive bacteria like methicillin-resistant S. aureus. The researchers used combinatorial synthesis methods to generate macroarrays comprising a library of chalcone-based small candidate molecules. These macroarrays use a Rink amide linker to attach the small molecules to a solid support. This allows additional chemical moieties to be covalently attached to the small molecules, further enhancing the diversity of the molecules that can be synthesized and screened. The Rink linker also results in the formation of an amide group on the small molecules that are released from the support, enhancing their water solubility and potentially their biological activity.

The resulting compound library was screened for antibacterial activity using an overlay technique, and the minimal inhibitory concentrations (MICs) of select compounds were quantified. Several antibacterial compounds were identified, including chalcone and chalcone derivatives such as alkylpyrimidine, aminopyrimidine and cyanopyridine. These compounds could be used to treat patients infected with bacteria, including drug resistant bacteria, and could also be used for sterilization and disinfection.

Synthetic Ligands Capable of Strongly Inhibiting or Inducing Quorum Sensing in Bacteria

UW-Madison researchers have developed non-native ligands that can block or imitate quorum sensing signals.  The ligands include N-phenylacetanoyl-L-homoserine lactones that are capable of inhibiting or strongly inducing quorum sensing in the bacterial symbiont Vibrio fischeri.  The invention also includes methods of using the synthetic ligands to treat infections or modulate biofilm formation.

Antibacterial Agents Using Small Molecule Macroarrays

UW-Madison researchers have developed novel chemical agents that exhibit potent antibacterial activity against MRSA and potentially other Gram-positive bacterial pathogens. To identify these compounds, the inventors developed a versatile discovery platform that couples array technology with high throughput screening techniques to simply and rapidly synthesize small molecules and screen them for antibacterial activity.

Method for Synthesizing Beta-Polypeptides from Functionalized Beta-Lactam Monomers

UW-Madison researchers have developed a robust method for making large quantities of poly-beta-peptides under mild and controllable conditions. The method involves polymerizing beta-lactams in an organic solvent. At least one of the monomers may comprise a fused, bicyclic beta-lactam moiety. A base initiator and a non-metal-containing co-initiator, such as an anhydride, are also present. This process was successfully used to synthesize a series of beta-peptide homopolymers and co-polymers, many of which exhibited antimicrobial activity.

Compounds and Methods for Modulating Communication and Virulence in Quorum Sensing Bacteria

UW-Madison researchers have developed a library of novel compounds that decrease the virulence of quorum sensing bacteria by blocking AHL binding. These non-native natural or synthetic AHL analogs bind to receptors in the cell membrane. With the receptors filled, the autoinducer ligand is blocked and gene expression, including biofilm formation, is inhibited, decreasing the likelihood of infection.

Antimicrobial Polymers

UW-Madison researchers have developed novel amphiphilic compounds that can be used to treat microbial infections in humans and other animals. They combined a synthetic backbone of poly(styrene), poly(acrylate), poly(acrylamide) or poly(C1-C6alkylene glycol) with side-chains that can readily accept a hydrogen atom to become water-soluble. These compounds inhibited the growth of four test microorganisms to the same extent as known antimicrobials.

Receptor For Bacillus anthracis Toxin

UW-Madison researchers have now provided the structure and sequence of the anthrax toxin receptor. The complete receptor includes an extracellular domain, a transmembrane domain and a cytoplasmic domain that can vary in length.

Identification of the sequence of the anthrax toxin receptor (ATR) will enable the detection and quantification of ATR mRNA and protein in a sample, and will also allow the generation of transgenic and knockout animals. This should lead to methods for treating human and non-human animals suffering from anthrax. For example, the inventors have demonstrated the therapeutic effectiveness of this invention by showing in tissue culture models that a soluble form of the receptor can block anthrax toxin by acting like a decoy.

A Supply of the Antibiotic Oligomycin

WARF has available for licensing a several hundred-gram quantity of the research chemical oligomycin. The available supply includes a mixture of oligomycins A, B and C, as well as purified preparations of oligomycin A and oligomycin B.