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      Ciprofloxacin Poly(β-amino ester) Conjugates Enhance Antibiofilm Activity and Slow the Development of Resistance

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          Abstract

          To tackle the emerging antibiotic resistance crisis, novel antimicrobial approaches are urgently needed. Bacterial biofilms are a particular concern in this context as they are responsible for over 80% of bacterial infections and are inherently more recalcitrant toward antimicrobial treatments. The high tolerance of biofilms to conventional antibiotics has been attributed to several factors, including reduced drug diffusion through the dense exopolymeric matrix and the upregulation of antimicrobial resistance machinery with successful biofilm eradication requiring prolonged high doses of multidrug treatments. A promising approach to tackle bacterial infections involves the use of polymer drug conjugates, shown to improve upon free drug toxicity and bioavailability, enhance drug penetration through the thick biofilm matrix, and evade common resistance mechanisms. In the following study, we conjugated the antibiotic ciprofloxacin (CIP) to a small library of biodegradable and biocompatible poly(β-amino ester) (PBAE) polymers with varying central amine functionality. The suitability of the polymers as antibiotic conjugates was then verified in a series of assays including testing of efficacy and resistance response in planktonic Gram-positive and Gram-negative bacteria and the reduction of viability in mono- and multispecies biofilm models. The most active polymer within the prepared PBAE-CIP library was shown to achieve an over 2-fold increase in the reduction of biofilm viability in a Pseudomonas aeruginosa monospecies biofilm and superior elimination of all the species present within the multispecies biofilm model. Hence, we demonstrate that CIP conjugation to PBAEs can be employed to achieve improved antibiotic efficacy against clinically relevant biofilm models.

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          The biofilm matrix.

          The microorganisms in biofilms live in a self-produced matrix of hydrated extracellular polymeric substances (EPS) that form their immediate environment. EPS are mainly polysaccharides, proteins, nucleic acids and lipids; they provide the mechanical stability of biofilms, mediate their adhesion to surfaces and form a cohesive, three-dimensional polymer network that interconnects and transiently immobilizes biofilm cells. In addition, the biofilm matrix acts as an external digestive system by keeping extracellular enzymes close to the cells, enabling them to metabolize dissolved, colloidal and solid biopolymers. Here we describe the functions, properties and constituents of the EPS matrix that make biofilms the most successful forms of life on earth.
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            Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America.

            The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews," and recently issued a "Call to Action" to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure--one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
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              Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies

              Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of morbidity and mortality in cystic fibrosis patients and immunocompromised individuals. Eradication of P. aeruginosa has become increasingly difficult due to its remarkable capacity to resist antibiotics. Strains of Pseudomonas aeruginosa are known to utilize their high levels of intrinsic and acquired resistance mechanisms to counter most antibiotics. In addition, adaptive antibiotic resistance of P. aeruginosa is a recently characterized mechanism, which includes biofilm-mediated resistance and formation of multidrug-tolerant persister cells, and is responsible for recalcitrance and relapse of infections. The discovery and development of alternative therapeutic strategies that present novel avenues against P. aeruginosa infections are increasingly demanded and gaining more and more attention. Although mostly at the preclinical stages, many recent studies have reported several innovative therapeutic technologies that have demonstrated pronounced effectiveness in fighting against drug-resistant P. aeruginosa strains. This review highlights the mechanisms of antibiotic resistance in P. aeruginosa and discusses the current state of some novel therapeutic approaches for treatment of P. aeruginosa infections that can be further explored in clinical practice.
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                Author and article information

                Journal
                ACS Appl Mater Interfaces
                ACS Appl Mater Interfaces
                am
                aamick
                ACS Applied Materials & Interfaces
                American Chemical Society
                1944-8244
                1944-8252
                30 January 2024
                07 February 2024
                : 16
                : 5
                : 5412-5425
                Affiliations
                []Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham , Nottingham NG7 2RD, U.K.
                []National Biofilms Innovation Centre, School of Life Sciences, Biodiscovery Institute, University Park, University of Nottingham , Nottingham NG7 2RD, U.K.
                [§ ]Department of Microbiology and Parasitology, Faculty of Biology-CIBUS, Universidade de Santiago de Compostela , Santiago de Compostela 15782, Spain
                []UCL School of Pharmacy, University College London , 29-39 Brunswick Square, London WC1N 1AX, U.K.
                Author notes
                Author information
                https://orcid.org/0009-0005-1751-685X
                https://orcid.org/0000-0002-6559-5514
                https://orcid.org/0000-0001-8337-1875
                Article
                10.1021/acsami.3c14357
                10859900
                38289032
                cf4e38f6-a46a-4d5d-9550-9b850d4e5e58
                © 2024 The Authors. Published by American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 25 September 2023
                : 05 January 2024
                : 17 December 2023
                Funding
                Funded by: Cystic Fibrosis Foundation, doi 10.13039/100000897;
                Award ID: SRC022
                Funded by: Hartree Centre, doi NA;
                Award ID: NA
                Funded by: Ministerio de Universidades, doi 10.13039/501100023561;
                Award ID: NA
                Funded by: Innovate UK, doi 10.13039/501100006041;
                Award ID: NA
                Funded by: Cystic Fibrosis Trust, doi 10.13039/501100000292;
                Award ID: SRC022
                Funded by: Biotechnology and Biological Sciences Research Council, doi 10.13039/501100000268;
                Award ID: BB/X002950/1
                Funded by: Biotechnology and Biological Sciences Research Council, doi 10.13039/501100000268;
                Award ID: BB/R012415/1
                Funded by: Wellcome Trust, doi 10.13039/100010269;
                Award ID: 108876/Z/15/Z
                Categories
                Research Article
                Custom metadata
                am3c14357
                am3c14357

                Materials technology
                polymer antimicrobials,antibiotic resistance,biofilms,quorum sensing,polymer–drug conjugates,combination anti-infectives

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