Combating bacterial ‘superbugs’ via latest experimental and computational approaches

Dr. Bulitta Lake NonaBacterial ‘superbugs’ which are resistant to most or all antibiotics present one of the three most serious threats to human health in the US and worldwide. This has been highlighted by the World Health Organization, the US President’s Office, the European Union, and numerous national and international organizations. If bacterial resistance to antibiotics is not tackled successfully, a tremendous financial loss (>$1 trillion till 2050), widespread human suffering and an increased mortality from bacterial infections have all been predicted. Without effective antibiotic therapy, care of premature neonates, transplants, cancer chemotherapy and many other achievements of modern medicine will no longer be possible without significant risk. Therefore, society is on a path of reverting back to the pre-antibiotic era.

To combat this substantial global health crisis, the dynamic antimicrobial research team at Lake Nona is developing innovative antibiotic combination therapies which can successfully treat infections by these ‘superbugs’. This team is headed by Dr. Jürgen Bulitta  who is an internationally recognized expert in antimicrobial pharmacology, latest in vitro infection models, and translational mechanistic modeling. His team is greatly enhanced by the in-depth expertise in molecular and clinical microbiology by Dr. Bartolome Moya as well as by multiple fruitful collaborations with the UF Institute for Therapeutic Innovation located in the same building at Lake Nona.

Drs. Bulitta and Moya have a long-standing interest in beta-lactam antibiotics which are the largest and most commonly used group of antibiotics. These drugs can be used safely in patients of all ages. However, there are substantial gaps in our understanding of how beta-lactam antibiotics can be used optimally which give rise to innovation combination therapies to combat ‘superbugs.’ This particularly applies to the use of two beta-lactams simultaneously. Such combinations can inactivate an optimal set of different target receptors (i.e. different penicillin-binding proteins). Additionally, our team is developing novel approaches of how to enhance the penetration of antibiotics to their bacterial target sites. This research involves the development of innovative combination therapies which include beta-lactam, aminoglycoside, polymyxin and other antibiotics, as well as a beta-lactamase inhibitor.

The second research stream by Dr. Bulitta’s group focuses on human pharmacokinetics, pharmacodynamics and toxicodynamics. This includes advanced models of oral and inhaled drug absorption and greatly benefits from Dr. Yuanyuan Jiao’s expertise in clinical pharmacy. The latter research includes a fruitful collaboration with Dr. Guenther Hochhaus (COP, UF) in a stream of FDA-funded clinical studies. The latter assess important properties of inhaled corticosteroid formulations. This research is highly important for the development of the much-needed generic formulations for inhaled drugs.

Dr. Bulitta is continuously developing a free, open-source facilitator tool (SADAPT-TRAN) which greatly supports Quantitative and Systems Pharmacology (QSP) modeling in the S-ADAPT software package. This tool greatly enhances the capabilities and efficiency of researchers worldwide to perform translational, mechanistic modeling and optimally dose patients. These approaches and concepts are taught in Dr. Bulitta’s new course on “Translational Clinical Pharmacology” (PHA6133).

Ongoing Projects

Translational antimicrobial pharmacology

NIH/NIAID R01 AI130185                  Bulitta JB (PI)                                   Role: PI
Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

FDA HHSF223201710199C               Luna BM (PI)                                   Role: Subaward-PI
A Preclinical Mouse Model of Acinetobacter baumannii Infection For Antibacterial Development

NIH/NIAID R01 AI111990                  Tsuji B / Li J (PD/PI)                        Role: Co-I
Novel PK/PD Strategies for Polymyxin Combinations against Gram-negative Superbugs

NHMRC APP1101553 Project           Landersdorfer CB (PI)                     Role: Co-I
Targeting hypermutable ‘superbugs’ in chronic respiratory infections by optimised antibiotic combination dosage regimens

State of Florida 7ZK30                        Brown AN (PI)                                 Role: Co-I
Identification of antiviral therapies for the treatment of Zika virus using existing drugs

Inhaled corticosteroids

FDA HHSF223201610099C               Bulitta JB (PI)                                   Role: PI
Pharmacokinetic Comparison of Locally Acting Orally Inhaled Drug Products

FDA U01 FD004943                           Hochhaus G (PI)                              Role: Co-PI
Comprehensive Evaluation of Formulation Effects on Metered Dose Inhaler Performance, Food and Drug Administration

FDA HHSF223201310220C               Hochhaus G / Bulitta J (PD/PI)       Role: PD/PI
Study to investigate the sensitivity of pharmacokinetics in detecting differences in physicochemical properties of the active in suspension nasal products for local action

Team Members

Jürgen B. Bulitta, PhD                    Antimicrobial Pharmacology, Chemistry

Postdocs
  • Bartolomé Moyá Cañellas, PhD  Molecular Microbiology
  • Yuanyuan Jiao, PhD  Clinical Pharmacist
  • Tae Hwan Kim, PhD Pharmaceutics, Bioanalytics
  • Dhruvitkumar S. Sutaria, PhD Molecular Pharmacology
  • Mong-Jen Chen, PhD Biochemist (Inhaled corticosteroid program with Dr. Hochhaus)
Ph.D. Students
  • Xun Tao, MSc Pharmaceutics, Bioanalytics
  • Stephanie Drescher, Pharmacist Pharmaceutics (Inhaled corticosteroids with Dr. Hochhaus)
  • Rajbharan Yadav, MSc Antimicrobial Pharmacology (at Monash University)
  • Vanessa Rees, BSc Antimicrobial Pharmacology (at Monash University)
Pharm.D. & Intern Students
  • Gustavo R. Alvira
  • Nred Dedaj
  • Brandon Klee
  • Kajetan Nierychlewski
  • Kristen Prince
  • Priscell Villegas