Optimization of Neoglycoside Antibiotics for Nosocomial Pathogens and Select Agen

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DESCRIPTION (provided by applicant): Multi-drug resistance in Gram-negative bacteria is a common problem in infected patients in the ICU environment. With Pseudomonas aeruginosa and Acinetobacter spp. it is not an uncommon event for there to be no antibiotics active for the organism, essentially returning us to the pre-antibiotic era. Resistance has also been defined in Select Agents, such as aminoglycoside resistance in Yersinia pestis in Madagascar. Achaogen has developed several series of new aminoglycoside antibiotics (neoglycosides). These agents have markedly improved activity against a wide variety of multi-resistant Gram-negative bacilli and also against Methicillin-Resistant Staphylococcus aureus (MRSA). In a different series, lead compounds have been identified with potent activity against Pseudomonas aeruginosa and Acinetobacter spp. It is the intent of this proposal to examine up to five of these molecules over the span of the proposal, rank order them and, for at least two of the molecules, to progress them into New Drug Applications. Aminoglycosides have become less used because of increasing resistance and their potential to cause nephrotoxicity. These neoglycosides obviate a great deal of the problems associated with resistance. In Specific Aim #1, we will employ our hollow fiber infection model to study candidate molecules. We can identify exposure targets that will result in optimal bacterial cell kill and suppression of resistant bacterial subpopulations. These targets will be identified through application of innovative large mathematical mixture models. In Specific Aim # 2, we will employ two animal models to validate these exposure targets. Because of the difference between murine and human half lives, we will employ a novel method of "humanizing" the drug administration in all animal models. These include a murine model of Gram-negative pneumonia and mouse thigh infection as a surrogate for skin/skin structure infection. This latter model will be run in both neutropenic and normal conditions. We will apply another completely novel model to all data, to understand pathogen kill by granulocytes. We will validate exposure targets from SA #1 with an understanding of the granulocyte impact. In Specific Aim #3, we developed a completely novel in vitro system with human proximal renal tubular epithelial cells (hPRTE cells) allowing generation of a concentration-time profile for any amino/neoglycoside that mimics the human urinary tract profile. By quantifying the amount of drug inside hPRTE cells over time and observing for apoptosis or necrosis, we can derive a relationship between drug exposure, duration and nephrotoxic event occurrence. Relationships between exposure and both effect and toxicity allows exploration of doses and durations to optimize these relationships simultaneously (maximal effect/ minimal toxicity). In Specific Aim # 4, we will employ population PK modeling with Monte Carlo simulation to identify optimal drug doses. Our aim is to bring at least 2 molecules to NDA with optimal doses/durations of therapy. Multi-resistant organisms have become a huge problem in patients with hospital-acquired infections. We intend to optimize the development of new aminoglycoside antibiotics (neoglycosides) to address this need and also to provide new products for the therapy of Select Agents, such as Plague, Anthrax and pathogens such as Burkholderia mallei and pseudomallei. We intend to identify an agent with very broad spectrum to address the infection problems associated with many of these pathogens. However, because Pseudomonas aeruginosa and Acinetobacter spp. are especially resistant and, hence, difficult to treat in seriously infected patients in the ICU setting, it is an aim of this proposal to identify an agent that is specifically optimized for extremely potent activity against these latter pathogens.