Dynamically crosslinked polymer nanocomposites to treat multidrug-resistant bacterial biofilms.
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ABSTRACT:
SUBMITTER: Zhu DY
PROVIDER: S-EPMC6190609 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Project description:The rapid emergence of antibiotic-resistant bacterial "superbugs" with concomitant treatment failure and high mortality rates presents a severe threat to global health. The superbug risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that render them refractory to available treatments. We hypothesized that efficient antimicrobial agents could be generated through careful engineering of hydrophobic and cationic domains in a synthetic semirigid polymer scaffold, mirroring and amplifying attributes of antimicrobial peptides. We report the creation of polymeric nanoparticles with highly efficient antimicrobial properties. These nanoparticles eradicate biofilms with low toxicity to mammalian cells and feature unprecedented therapeutic indices against red blood cells. Most notably, bacterial resistance toward these nanoparticles was not observed after 20 serial passages, in stark contrast to clinically relevant antibiotics where significant resistance occurred after only a few passages.
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Project description:IntroductionGuidelines for treatment of multidrug-resistant (MDR) bacteria rely on newly approved antibiotics, with limited evidence of their effectiveness for treating these infections. Data regarding cost of such an approach are lacking. We aimed to evaluate estimated cost of using newly approved antibiotic drugs compared to older antibiotics for the treatment of difficult-to-treat pathogens.MethodsMDR bacteria of interest included those defined by the World Health Organization as critical or of high priority for research. Old and newly approved antibiotics for these bacteria, defined as approved before or after January 2010, respectively, were evaluated for treatment cost and for 14-day treatment course. Estimated annual costs were calculated based on the Centers for Disease Control and Prevention's' report on MDR bacteria prevalence in US hospitalized patients. Old and new drugs costs were compared.ResultsThe cost of a 14-day treatment course for methicillin-resistant Staphylococcus aureus bacteremia with a newly approved drug was found to be 6 to 60 times higher than that of older drugs. Similarly, the cost of a 14-day course for carbapenem-resistant Enterobacterales or MDR Pseudomonas aeruginosa was doubled with new drugs; and for carbapenem-resistant Acinetobacter baumannii, ~ 20 times higher with newer drugs. Annual incremental costs of treating difficult-to-treat Gram-negative bacteria with new drugs ranged from 30 million to over 500 million USD.ConclusionsUsing newly approved antibiotic drugs for MDR infections carries a large incremental cost. Additional data to support survival benefit of these drugs are required to justify the price differences. Subgroups of patients who would benefit most from treatment should be defined.
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Project description:Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.
| S-EPMC7339739 | biostudies-literature
Project description:BackgroundThe "One Health" concept recognizes that human health and animal health are interdependent and bound to the health of the ecosystem in which they (co)exist. This interconnection favors the transmission of bacteria and other infectious agents as well as the flow of genetic elements containing antibiotic resistance genes. This problem is worsened when pathogenic bacteria have the ability to establish as biofilms. Therefore, it is important to understand the characteristics and behaviour of microorganisms in both planktonic and biofilms states from the most diverse environmental niches to mitigate the emergence and dissemination of resistance.MethodsThe purpose of this work was to assess the antibiotic susceptibility of four bacteria (Acinetobacter spp., Klebsiella pneumoniae, Pseudomonas fluorescens and Shewanella putrefaciens) isolated from wild animals and their ability to form biofilms. The effect of two antibiotics, imipenem (IPM) and ciprofloxacin (CIP), on biofilm removal was also assessed. Screening of resistance genetic determinants was performed by PCR. Biofilm tests were performed by a modified microtiter plate method. Bacterial surface hydrophobicity was determined by sessile drop contact angles.ResultsThe susceptibility profile classified the bacteria as multidrug-resistant. Three genes coding for ?-lactamases were detected in K. pneumoniae (TEM, SHV, OXA-aer) and one in P. fluorescens (OXA-aer). K. pneumoniae was the microorganism that carried more ?-lactamase genes and it was the most proficient biofilm producer, while P. fluorescens demonstrated the highest adhesion ability. Antibiotics at their MIC, 5 × MIC and 10 × MIC were ineffective in total biofilm removal. The highest biomass reductions were found with IPM (54% at 10 × MIC) against K. pneumoniae biofilms and with CIP (40% at 10 × MIC) against P. fluorescens biofilms.DiscussionThe results highlight wildlife as important host reservoirs and vectors for the spread of multidrug-resistant bacteria and genetic determinants of resistance. The ability of these bacteria to form biofilms should increase their persistence.
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