Neisseria gonorrhoeae (Ng) is associated with high morbidity and socioeconomic consequences, remaining a major public health concern in the United States and worldwide. Current clinical isolates have developed resistance to antimicrobials previously recommended for first-line treatment;thus, an era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health concern. The objective of this proposal is to identify novel antibacterial compounds/extracts from several pre-existing target-based and natural product-based projects, and to determine the suitability of anti-Ng compounds for further development by medicinal chemistry optimization and animal efficacy studies. The innovation in our approach lies in the fact that we will be targeting antibacterial mechanisms in Ng that have not yet been clinically targeted, and are therefore not likely to be susceptible to pre-existing clinical resistance. Antibacterial agents from several Cubist discovery programs will be used in this proposal inhibit essential enzymes in Gram-negative and Gram-positive bacteria. In addition we will use fractionated extracts derived from a collection of Actinomycetes prescreened to have activity against a proprietary E. coli strain engineered to be resistant to many known natural product antibiotics.
Aim 1 : Identify novel antibiotics in an existing collection that have activity against Neisseria gonorrhoeae. We will perform MIC testing of candidate compounds and extracts against susceptible laboratory strains of Ng. The top 20% of compounds based on MIC value will be tested against the wider 17 strain Ng panel including drug-resistant isolates. Compounds with favorable MICs against drug-resistant strains will advance to MIC testing against panels of clinically-relevant and further drug-resistant Ng isolates. An assessment of spontaneous resistance frequencies will also be employed to prioritize scaffolds. The main purpose of this aim is to determine the potency of 80 compounds having antibacterial mechanisms of action that are distinct from current and past clinically exploited mechanisms.
Aim 2 : Determine the suitability of anti-Ng compounds for further development. The main goal of this aim is to profile the physical, chemical and PK/ADME characteristics of compounds and extract hits from Aim 1. We will determine baseline properties of the molecules and opportunities for further development, including solubility, chemical stability, permeability, plasma stability, protein binding, pharmacokinetics in mice, and tolerability in mice. Taken together, all of these characteristics of compounds will define their suitability for testing in an experimental animal model of urogenital gonorrhea.
Aim 3 : Assessment of the efficacy of compounds in a mouse model of urogenital Ng infection. Compounds that have properties amenable to testing in mice will be assessed in an experimental Ng mouse infection model previously published by our collaborator, Dr. Jerse. This model has been established and validated using test agents known to be clinically successful against urogenital Ng infection. As such, the model is deemed to be translational to the clinical setting.
Neisseria gonorrhoeae (Ng) is the second most commonly reported communicable disease in the United States, with an estimated incidence of more than 600,000 cases annually. Ng is associated with high morbidity and socioeconomic consequences, remaining a major public health concern worldwide. Resistance of Ng to approved therapies has recently emerged and will likely spread globally within the next decade. The objective of this proposal is to characterize novel antibacterial compounds/extracts from several pre-existing target- based and natural product-based projects, and determine their suitability as anti-Ng compounds for further development by microbiological characterization, medicinal chemistry optimization and animal efficacy studies.