Metallo-β-lactamases: structure, function, epidemiology, treatment options, and the development pipeline

Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance in vivo, under zinc limitation, than in vitro. Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review

Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate´s phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.J.T.S. holds a research contract from the Fundación para la Formación e Investigación de los Profesionales de la Salud de Extremadura (FundeSalud), Instituto de Salud Carlos III. M.F.R. holds a clinical research contract “Juan Rodés” (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III

The de novo design and stabilization of self-assembling helix bundle proteins and the dissociative inhibition of HIV-1 protease

A series of peptides capable of self-assembling into helix bundle proteins was designed, synthesized, and studied. The peptide Leu4 was shown to exist primarily as a parallel two-helix bundle in aqueous solution. The peptide Leu6 was shown to form a four- or five-helix bundle in aqueous solution, and the peptide Leu8 was shown to form an eight-helix bundle in aqueous solution. The study showed that the size of bundle formed by a amphiphilic peptide is directly related to the size of the apolar face. These design aspects were then extended to the design of a peptide, L6HC, capable of cross-linking a helix bundle using a homocysteine residue. While it was designed to cross-link a four-helix bundle, L6HC formed a covalently cross-linked five-helix bundle as the major product, but also formed other covalently cross-linked four- and five-helix bundles. The peptide design was revaluated by replacing the homocysteine residue with the next higher homolog, (R)-2-amino-5-mercaptobutanoic acid, and cysteine. The peptide containing the (R)-2-amino-5-mercaptobutanoic acid, L6HHC, formed covalently cross-linked four- and five-helix bundles and the cysteine peptide was not capable of forming a cross-linked bundle, but instead formed a intrahelical disulfide bond. An inhibitor capable of inhibiting HIV-1 protease activity by dissociating the enzyme dimer was also synthesized. This inhibitor was a refinement of a previous inhibitor, and used a steroid tether to link two short peptides. The refinement, based on molecular modeling, incorporated a bend in the structure of a rigid steroid to allow a better fit of the inhibitor molecule and a monomer of the protease. The inhibitor showed a minimal improvement in IC\sb{50} compared to the original inhibitor on which it was based

Ground and On-Orbit Calibration of High Accuracy Stellar Navigation Sensors

Stellar navigation using star trackers require precise radiometric and spatial calibration of the instrument over multiple environmental variables. Calibration accuracy is critical for high performance star trackers such as the Ball High Accuracy Star Tracker (HAST). This paper discusses calibration methods and capabilities that allow for sub-tenths of seconds of arc performance achieved by the HAST

Assessing the Potential for Unintended Microbial Consequences of Routine Chlorhexidine Bathing for Prevention of Healthcare-associated Infections

AbstractChlorhexidine gluconate (CHG) is an antiseptic that is widely used in healthcare due to its excellent safety profile and wide spectrum of activity. Daily bathing with CHG has proven to be effective in the prevention of healthcare-associated infections and multidrug-resistant pathogen decolonization. Despite the proven benefits of CHG use, there remain concerns and unanswered questions about the potential for unintended microbial consequences of routine CHG bathing. This review aims to explore some of these questions.</jats:p