Monitoring of multidrug-resistant Gram-negative bacteria of medical importance (human & veterinary): clinical/environmental impact and development of therapeutic alternatives and technology innovation products

Abstract

The emergence of multidrug-resistant bacteria (MDR) is a global public health issue, consequence of the overuse and misuse of antibiotics. Following the Darwinian principle of survival of the fittest this practice has favored the natural selection and endemicity of MDR bacterial in clinical settings (human and veterinary), whereas the rapid spread of genes encoding new and broad-spectrum mechanisms of resistance has contributed to therapeutic failure. In this context, Brazil has been one of the most affected countries, which has been discussed repeatedly in scientific meetings, with data widely documented in national and international journals, where carbapenemase (IMP-1, OXA -23, OXA-143, SPM-1 or KPC-2)- and/or extended-spectrum beta-lactamases (CTX-M-type)-producing gram-negative bacteria are associated with high morbidity and mortality rates and outbreaks of hospital infection. Although clinical, microbiological and epidemiological data related to MDR bacteria and health care-associated infections (HCAI) have been elucidated, the environmental impact and the potential role of reservoirs (i.e., environmental sources, pets or food-producing animals) in very close contact with human beings has been neglected and needs to be evaluated with priority. Thus, the aim of this study is to monitor the prevalence of MDR gram-negative bacteria, with transferable plasmid-mediated resistance to human and veterinary broad-spectrum beta-lactam and fluoroquinolone agents, in clinical samples, aquatic environments and companion animals in São Paulo state, elucidating the clonal relationships, and proposing alternative therapies based on bactericidal activity of drug combinations exhibiting a synergistic effect; use of bilayer fragments of cationic lipids (bicelles); lytic bacteriophages; biomimetic bacteriophage nanoparticles (patent request PI: 1020120238152), and/or their combinations, under physicochemical conditions supporting the development of pharmaceutical products of technological innovation, with potential useful applications. The results will contribute to epidemiological data on resistance to antibiotics in bacteria that can be isolated from aquatic public environments and companion animals, determining the clinical/environmental impact resulting from the overuse and misuse of compounds with antimicrobial activity; identifying the sources/vehicles and public places with potential for human transmission, or to spread to other animals or associated ecosystems in the city of São Paulo. Moreover, search for therapeutic alternatives will contribute to the establishment of therapeutic schedules and/or recommendations for the use of effective antibiotic combinations for the treatment of infections produced by MDR bacteria, which have become endemic in Brazil. Finally, physicochemical and antibacterial studies of bilayer fragments of cationic lipids, nanoparticles, and lytic bacteriophages, against MDR bacteria, will provide the basis for development of pharmaceutical products of technological innovation with potential clinical applicability. (AU)