Phillips J.B.,University of Montana |
Smith A.E.,Promiliad Biopharma, Inc. |
Kusche B.R.,Promiliad Biopharma, Inc. |
Bessette Jr. B.A.,Promiliad Biopharma, Inc. |
And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010
We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis. © 2010 Elsevier Ltd. All rights reserved.
Sumskaya Y.G.,University of Connecticut |
Swain P.W.,Promiliad Biopharma, Inc. |
Bergmeier S.C.,Promiliad Biopharma, Inc. |
McMills M.C.,Promiliad Biopharma, Inc. |
And 2 more authors.
Arkivoc | Year: 2011
We have been interested in the application of readily available, fermentation-derived natural products as key building blocks for the preparation of natural product-like libraries rich in structural and stereochemical diversity. In this manuscript we describe the conversion of methyl nonactate, derived from nonactin, to a diversable scaffold characteristic of macrolide natural products. The synthesis features a key ring-closing metathesis reaction to form the macrocycle. © ARKAT-USA, Inc.
Zachary Oblak E.,University of Connecticut |
Bolstad E.S.D.,Promiliad Biopharma, Inc. |
Ononye S.N.,University of Connecticut |
Priestley N.D.,Promiliad Biopharma, Inc. |
And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2012
A direct route to analogs of the naturally occurring tropolone β-thujaplicin has been developed in just four steps from furan. Using this method, a series of derivatives were synthesized and evaluated. Several of these compounds demonstrated very high levels of potency against bacterial and fungal pathogens with good selectivity over mammalian cells. © 2012 The Royal Society of Chemistry.
Viswanathan K.,University of Connecticut |
Frey K.M.,University of Connecticut |
Scocchera E.W.,University of Connecticut |
Martin B.D.,Promiliad Biopharma, Inc. |
And 5 more authors.
PLoS ONE | Year: 2012
Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 μg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin. © 2012 Viswanathan et al.
Luesse S.B.,Promiliad Biopharma, Inc. |
Wells G.,Promiliad Biopharma, Inc. |
Miller J.,Ohio University |
Bolstad E.,Promiliad Biopharma, Inc. |
And 4 more authors.
Combinatorial Chemistry and High Throughput Screening | Year: 2012
The 7-oxabicyclo[2.2.1]heptene ring system is a common structural motif in many pharmacologically interesting molecules. We recognized the potential to employ this highly oxygenated and conformationally-restricted scaffold in diversity-oriented synthesis to generate a library of non-chiral but topologically complex compounds. Herein, we report the synthesis and biological evaluation of two 96-member tricyclic libraries containing the oxabicyclo[2.2.1]heptene framework using acetal formation as the key step. © 2012 Bentham Science Publishers.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 295.73K | Year: 2016
DESCRIPTION provided by applicant Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease The resistance problem is compounded by the lack of discovery of new antibiotics especially those with novel mechanisms of action New antibiotics are critically needed as resistance to recently developed antibiotics is growing The goal of this project is to develop our triazolononactate antibiotics as exemplified by our lead compound PBI G as broad spectrum agents active against Gram positive pathogens Specifically we will improve the antibacterial activity and selectivity of our current lead compounds against S aureus including MRSA E faecalis including VRE and S pyogenes We will obtain data that will allow us to make a hypothesis concerning the MOA of the triazolononactate compound class and to identify the target so that we may employ structure based drug design to achieve our goals of potency and spectrum of activity In addition to using classic tracer studies we will use several resistant bacterial strains in hand to determine the genetic modifications leading to resistance Beyond the improvement of potency and identification of the cellular target we will initiate DMPK studies to determine if the triazolononactate compound class has any critical liabilities such as metabolic instability a poor resistance profile or off target pharmacology We will determine the maximal tolerated dose and basic pharmacodynamic properties Cmax AUC t oral bioavailability of the compound class We will then assess whether our best compounds show effectiveness in a murine S aureus infection model In summary this Phase I project seeks to obtain analogs of our lead compound that have improved potency and selectivity identify a mechanism of action and to evaluate DMPK properties We envisage a Phase II project wherein we fully address ADMET issues and greatly expand animal studies with an improved compound set to move our compound class to our eventual goal of an IND filing PUBLIC HEALTH RELEVANCE The ability to treat infections has become compromised by growing resistance to current antibiotics and has become a serious threat to public health The significance of the threat is greater as there have been fewer antibiotics being approved for use in recent years and the discovery of a new class of antibiotic is a rare event By employing natural product chemistry we have been able to identify a set of novel antibiotics These compounds are active against a range of pathogens including methicillin resistant Staphylococcus aureus MRSA This project seeks to demonstrate that these compounds can be developed into drugs
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 287.77K | Year: 2013
DESCRIPTION: Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the relative lack of discovery of new antibiotics, especially those with novel mechanisms of action. Over the past several years Promiliad Biopharma has been developing new inhibitors that target the enzyme dihydrofolate reductase as a method of treatment for pathogenic bacteria, fungi and protozoa. Throughour efforts and those of our collaborators, largely funded by STTR grants, we have discovered a class of antifolates characterized by a 2, 4- diaminopyrimidine and a biaryl domain linked through a three-atom propargyl bridge. This class of molecules is animportant lead in the discovery of a new treatment for infectious disease. The current class of compounds, while potent antibacterial agents with activity against antibiotic resistant pathogens, currently lack sufficient metabolic stability. These compounds have short in vivo (and in vitro) half-lives which make progression to lead compound status somewhat difficult. We have found that by substituting a key fragment of the structure with a non-metabolizable bioisostere we can retain potency against a rangeof Gram positive pathogens while greatly improving selectivity and metabolic half-life. The goal of this project is o design, synthesize and assay additional bioisosteric analogs which display similar or better improvements in potency, metabolism and physical properties. Our goal in this Phase I application is to obtain a clear lead candidate. A Phase II project continuing from this work would then conduct IND-enabling experiments with the clear goal of filing an IND application. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The ability to treat infections has become compromised by growing resistance to current antibiotics and has become a serious threat to public health. The significance of the threat is greater as there have been fewer antibiotics being approved for use in recent years and the discovery of a new class of antibiotic is a rare event. By employing medicinal chemistry we have been able to develop a set of second generation folate antibiotics based upon the structure of trimethoprim. These compounds are active against a range of pathogens including methicillin-resistant Staphylococcus aureus (MRSA). This project seeks to develop a clear lead candidate that will undergo preclinical evaluation with the ultimate goal of entering clinical trials.