Fine Chemicals Angeles Farrań,† Chao Cai,‡ Manuel Sandoval, Yongmei Xu, Jian Liu, María J. Hernaíz,* and Robert J. Linhardt* †Departamento de Química Orgańica y Bio-Orgańica, Facultad de Ciencias, Universidad Nacional de Educacioń a Distancia, Paseo Senda del Rey 4, 28040 Madrid, Spain ‡Key Laboratory of Marine Drugs of Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China Escuela de Química, Universidad Nacional of Costa Rica, Post Office Box 86, 3000 Heredia, Costa Rica Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States Center for Biotechnology & Interdisciplinary Studies and Department of Chemistry & Chemical Biology, Rensselaer Polytechnic Institute, Biotechnology Center 4005, Troy, New York 12180, United States Departamento de Química Orgańica y Farmaceútica, Facultad de Farmacia, Universidad Complutense de Madrid, Pz/Ramoń y Cajal s/n, 28040 Madrid, Spain

Green solvents in carbohydrate chemistry: from raw materials to fine chemicals.

Antimicrobial peptides (AMPs), critical components of the innate immune system, are widely distributed throughout the animal and plant kingdoms. They can protect against a broad array of infection-causing agents, such as bacteria, fungi, parasites, viruses, and tumor cells, and also exhibit immunomodulatory activity. AMPs exert antimicrobial activities primarily through mechanisms involving membrane disruption, so they have a lower likelihood of inducing drug resistance. Extensive studies on the structure-activity relationship have revealed that net charge, hydrophobicity, and amphipathicity are the most important physicochemical and structural determinants endowing AMPs with antimicrobial potency and cell selectivity. This review summarizes the recent advances in AMPs development with respect to characteristics, structure-activity relationships, functions, antimicrobial mechanisms, expression regulation, and applications in food, medicine, and animals.

Antimicrobial peptides: Promising alternatives in the post feeding antibiotic era.

Ciprofloxacin derivatives and their antibacterial activities

Deoxy-sugars often play a critical role in modulating the potency of many bioactive natural products. Accordingly, there has been sustained interest in methods for their synthesis over the past several decades. The focus of much of this work has been on developing new glycosylation reactions that permit the mild and selective construction of deoxyglycosides. This Review covers classical approaches to deoxyglycoside synthesis, as well as more recently developed chemistry that aims to control the selectivity of the reaction through rational design of the promoter. Where relevant, the application of this chemistry to natural product synthesis will also be described.

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Methods for 2-Deoxyglycoside Synthesis.

The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.

Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy

Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin–moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classe...

Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux

Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria. Mode-of-action studies indicate that AAGs predominately target bacterial membranes, thereby leading to depolarization and increased permeability. To assess whether AAGs also induce host-directed immunomodulatory responses, we determined the AAG-dependent induction of cytokines in macrophages in the absence or presence of lipopolysaccharide (LPS). Our results show for the first time that AAGs can boost the innate immune response, specifically the recruitment of immune cells such as neutrophils required for the resolution of infections. Moreover, AAGs can selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock. In conclusion, our study demonstrates that AAGs possess multifunctional properties that combine direct antibacterial activity with host-directed clearance effects reminiscent of those of host-defense peptides.

Goutam Guchhait

Papers

Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy

Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux

Amphiphilic Tobramycins with Immunomodulatory Properties

Efficient glycosylation of unprotected sugars using sulfamic acid: A mild eco-friendly catalyst

Efficient acylation and sulfation of carbohydrates using sulfamic acid, a mild, eco-friendly catalyst under organic solvent-free conditions