Antibacterial Activity of Novel Prodrugs of Amoxicillin and Cephalexin

Two novel prodrugs of amoxicillin and cephalexin (amoxicillin ProD 1 and cephalexin ProD 1, respectively) were designed and synthesized to improve the stability and bitter sensation of their parent drugs. The in vitro susceptibility for both prodrugs was determined against Escherichia coli, staphylococcus epidermidis, staphylococcus aureus, Klebsiella pneumonia, streptococcus group A and streptococcus group B, and was compared to that of their active parent drugs.The antibacterial screening demonstrates that amoxicillin ProD 1 and cephalexin ProD 1 were found to be active and are considered among a small number of prodrugs that have therapeutic activity themselves before undergoing interconversion via enzymatic or chemical reaction to their corresponding active parent drugs. Both prodrugs exhibit their antibacterial activity against different types of bacterial strains due to the presence of β- lactam ring in their structures. In addition, it is expected that these novel prodrugs will be much more stable in aqueous media than their corresponding active parent drugs due to the fact that the chemically sensitive amine group contained in the active parent drug structures is replaced with an amide, more chemically stable group, in the corresponding prodrugs

Antimicrobial biomaterials for treatment of bone and implant infections

Implant-associated infections are devastating complications. The implant surface is very easy to be colonized by bacteria, which then form a biofilm. The biofilm on the implant surface is difficult to eradicate. Therefore, the prevention procedures for an implant surface are of crucial importance. Prevention of the implants begins with knowledge of the factors that cause the risk of infection, which can lead to the development of infection in different stages: preoperatively, intraoperatively, or postoperatively. The systemically injected antibiotic spreads through the entire body. As a result, the concentration, which arrives at the infection site is mainly sublethal. The insufficient dosage of such antimicrobials leads to unresolved infection because it often does not reach the infected site. Therefore, there is a critical need for a novel solution, either one, which allows the drug to reach the infection with high concentration and improve the biofilm penetration or the one, which helps the implant surface hinder bacteria colonization. In this PhD work few strategies for biofilm-based infections were introduced: prodrug antibiotic local delivery based on biorthogonal chemistry, antimicrobial coating against S.aureus utilizing the inverse-electron demand Diels-Alder reaction and MI-dPG polymer, antifungal impregnated PMMA bone cement against Candida spp. biofilms and electro-responsive hydrogels with photosensitizer curcumin release against MRSA.Implantat-assoziierte Infektionen können zu verheerenden Komplikationen führen. Die Implantatoberfläche lässt sich sehr leicht von Bakterien besiedeln, die dann einen Biofilm bilden. Der Biofilm auf der Implantatoberfläche ist schwer zu beseitigen. Daher sind die Präventionsverfahren für eine Implantatoberfläche von entscheidender Bedeutung. Die Prävention der Infektion beginnt mit dem Wissen über die Infektionsverursachenden Faktoren, welche präoperative, intraoperative sowie postoperative Infekte verursachen können. Systemisch injizierte Antibiotika haben zum Nachteil, dass sie sich im gesamten Körper verteilen und somit nur eine geringe Dosis der Anfangskonzentration am Infektionsort ankommt. Die unzureichende Dosierung solcher antimikrobieller Mittel führt zu einer ungelösten Infektion. Daher besteht ein dringender Bedarf an neuartigen Lösungen, entweder eine, die es dem Medikament ermöglicht, die Infektion mit hoher Konzentration zu erreichen und die Biofilmdurchdringung zu verbessern, oder eine andere, die dazu beitragen kann, die Implantatoberfläche vor einer Bakterienbesiedlung zu schützen. In dieser Doktorarbeit werden einige Strategien gegen biofilmbasierte Infektionen vorgestellt: lokale Prodrug Antibiotika Verabreichung basierend auf bioorthogonale Chemie, antimikrobielle Beschichtung gegen S. aureus unter Verwendung der Diels-Alder-Reaktion mit inversem Elektronenbedarf und MI-dPG-Polymer, antimykotisch imprägnierte PMMA Knochenzemente gegen Candida Biofilme und elektroreaktive Hydrogele mit photosensibler Curcumin Freisetzung gegen methicillinresistente S. aureus

Mucin binding reduces colistin antimicrobial activity

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance

Optimizing antimicrobial drug dosing in critically ill patients

Funding Information: Conflicts of Interest: P.P. has received lecture fees and advisory board from MSD, Gilead, Pfizer; L.C. and P.M. declared no conflicts of interest related to the underlying topics; J.G.P. received unre‐ stricted research grants from Merck Sharp and Dohme; received lecture and advisory board fees from Merck Sharp and Dohme, Angelini Pharmaceuticals; lecture fees from Pfizer Pharmaceuticals, Atral Pharmaceuticals, Biomerieux. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.publishersversionpublishe

Amino acids in the development of Prodrugs

Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.NV acknowledges support from Fundação para a Ciência e Tecnologia (FCT, Lisbon, Portugal) and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. NV also thanks FCT for the IF position and Fundação Manuel António da Mota (FMAM, Porto, Portugal) and Pfizer (Portugal) for support for the Nuno Vale Research Group. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT, FMAM and Pfizer

Functional Polymers as Innovative Tools in the Delivery of Antimicrobial Agents

This Special Issue explored different topics concerning recent progress in the synthesis and characterization of suitable innovative macromolecular systems, proposed as carriers of specific antimicrobial molecules, to be employed in the biomedical and pharmaceutical fields. Many infectious diseases are induced by omnipresent micro-organisms, including bacteria, viruses, protozoa, fungi, and algae, and, consequently, are very common, accounting for a significant share of the global disease burden. Unfortunately, antimicrobial resistance, adverse effects, and the high cost of antimicrobials are crucial health challenges worldwide. One of the common efforts in addressing this issue lies in improving the existing antimicrobial delivery systems. In this regard, nanoparticles as well as three-dimensional hydrophilic systems represent valuable tools able to ensure excellent performances. Biocompatible polymeric particles, entrapping these bioactive molecules, are capable of releasing them over a desired period of time, thereby decreasing the frequency of their administration. At the same time, these systems are able to protect antimicrobial drugs from degradation, enhancing their bioavailability. This Special Issue serves to highlight and capture the contemporary progress recorded in this field

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs

Therapeutic Applications of Bioconjugates in Human Disease

The unifying element tying together the therapeutics presented in this thesis is annexin A5. The protein, annexin 5 (ANXA5), is a membrane management protein that specifically binds to apoptotic cells. The natural ligand of ANXA5 displayed by apoptotic cells is phosphatidylserine. The aminophospholipid phosphatidylserine (Ptd-L-Ser) is a universal marker of mammalian cell stress. The expression of Ptd-L-Ser is triggered by a diverse range of cellular pathologies, most notably cellular trauma, oncogenesis, or infection. Annexin plays several critical roles in the pathogenicity of these disease states. Our previous work has demonstrated that ANXA5 derived therapeutics can be targeted to Ptd-L-Ser expression. In this thesis I build on this work, targeting several novel bioconjugates to Ptd-L-Ser expression

Recent Advances of Mechanical Engineering Applications in Medicine and Biology

Background: Mechanics is an area of science dealing with the behavior of physical bodies (solids and fluids) undergoing action of forces, it comprised of statics, kinetics and kinematics.  The advances and research in Applied Mechanics has wide application in almost fields of study including medicine and biology. In this paper, the relationship between mechanical engineering and medicine and biological sciences is investigated based on its application in these two sacred fields. Some emergent mechanical techniques applied in medical sciences and practices are presented. Methods: Emerging applications of mechanical engineering in medical and biological sciences are presented and investigated including: biomechanics, nanomechanics and computational fluid dynamics (CFD). Results: This review article presents some recent advances of mechanical engineering applications in medicine and biology. Specifically, this work focuses on three major subjects of interests:  Biomechanics that is increasingly being recognized as an important application of mechanical fundamentals in biomedical and biological sciences and practices, biomechanics can play a crucial role in both injury prevention as well as performance enhancement of living systems. Novel techniques of nanomechanics including: Carbon nanotubes  applications in therapy, DNA recognition, immunology and antiviral resistance. Nanorobotics that combines between nanotechnology, mechanics and new biomaterials to design and develop nanorobots based bacteria and biochips; these nanoscale robots can be involved in biomedical applications, particularly for the treatment of cancer, cerebral aneurysm treatment, kidney stones removal surgery, treatment of pathology, elimination of defected parts in the DNA structure, and some other treatments to save human lives. Computational fluid dynamics (CFD) tools that contribute on the understanding of blood flows, human organs dynamics and surgical options simulation. Conclusion: Recent advances of mechanical applications in medicine and biology are carried out in this review, such as biomechanics, nanomechanics and computational fluid dynamics (CFD). As perspectives, mechanical scholars and engineers can involve these cited applications in their researches to solve many problems and issues that doctors and biologists cannot

Chemical and biological evaluation of antibiotic-based ionic liquids and GUMBOS against pathogenic bacteria

The research presented in this dissertation explores a novel pragmatic therapeutic approach for control, prevention, and treatment of infectious disease using Active-Pharmaceutical Ingredient-based Ionic Liquids (API-ILs) and Groups of Uniform Materials Based on Organic Salts (GUMBOS). Accordingly, several antiseptic- and antibiotic-based API-ILs and GUMBOS were synthesized and characterized using a combination of analytical and microbiological techniques. Overall, this research presents an advanced alternative to combination antibiotic therapy by using a novel group of ionic antimicrobial materials that have controlled pharmacokinetics, improved bioavailabilities, reduced toxicities, multi-modal properties, and potent antimicrobial spectrum of activity as a viable alternative to combating bacterial infections. The first part of this research provides the physical characterization and subsequent in vitro antimicrobial activity of ampicillin-based ILs consisting of several different quaternary ammonium compounds (QACs) on Escherichia coli O157:H7, Klebsiella pneumoniae, Staphylococcus aureus, and Listeria monocytogenes. The synthesized API-ILs were validated with proton nuclear magnetic resonance spectroscopy (NMR) and elemental analysis. Melting points, critical micelle concentrations, and solubility were among the other physical properties investigated. Improved antibacterial activity was evaluated using Loewe’s Additivity Mathematical Model and interaction indices were established and compared to mixtures of precursor QACs and ampicillin. The second part of the dissertation research focuses on the synthesis and antibacterial activity of GUMBOS created from an antiseptic and several â-lactam antibiotics. Using anion metathesis, four â-lactam antibiotic-based chlorhexidine GUMBOS were synthesized prior to validation using proton and carbon NMR, mass spectrometry, elemental analysis, and absorbance spectroscopy. Several orders of improvement in in vitro antibacterial activities were obtained on isolates of Escherichia coli O157:H7, Salmonella typhi, Acinetobacter baumanii, Enterobacter clocae, Enterobacter aerogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marscescens, Staphylococcus aureus, Streptococcus mutans Streptococcus facaelis, Micrococcus luteus, Bacillus cereus, and Methicillin-resistant Staphylococcus aureus. Interaction indices show the GUMBOS to be synergetic ion-pairs despite additivity and antagonism observed by the mixtures of antiseptic and antibiotic precursor ions. Furthermore, the mechanisms of action studies for these materials were defined with emphasis on membrane permeability and membrane potential. Finally, acute cytotoxicity against fibroblast, endothelium, and cervical cellular lines in addition to an assessment of intestinal permeability and bioavailability were completed