Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or ribosomal RNA methyl transferases.
With a view to facilitating prediction of the exocyclic bond to the pyranoside ring in higher carbon sugars, a model is advanced that relates the relative configuration of the three stereogenic centers comprised of the branchpoint and of the two flanking centers (C4−C5−C6 in aldoheptoses and higher and C5−C6−C7 in sialic and ulosonic acids) to that of the simple ringopened pentoses. Assignment of a given stereotriad as arabino, lxyo, ribo, or xylo by inspection of the Fischer projection formulas permits prediction of conformation of the exocyclic bond by comparison with the known solution (= crystal in all cases) conformations of the simple pentitols. More remote stereogenic centers in the side chain, as in the 8-position of N-acetylneuraminic acid, have little impact on the conformation of the exocyclic bond. On the basis of this model the conformation of the exocyclic bond in ring I of 6′-homologated 4,5-disubstituted 2-deoxystreptamine class aminoglycoside antibiotics was predicted and was borne out by NMR analysis of newly synthesized derivatives in D 2 O at pD5. The antiribosomal and antibacterial activity of these derivatives is briefly presented and discussed in terms of preorganization of the side chain for binding to the ribosomal decoding A site. It is anticipated that this predictive analysis will also find use in the prediction of the conformation of the exocyclic bonds in other 2-(1hydroxyalkyl)-3-hydroxytetrahydropyrans and tetrahydrofurans.
Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe
acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans
causing zoonotic outbreaks of severe disease. Both viruses originate from a group of
betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens
from this group along with previous studies illustrating the potential of other subgroup
2b members to transmit to humans has underscored the need for antiviral development
against them. Coronaviruses modify the host innate immune response in part through the
reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To
identify unique or overarching subgroup 2b structural features or enzymatic biases, the
PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and
structurally evaluated. This evaluation revealed that PLpros from subgroup 2b
coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15
originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool
alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup
2b PLpro inhibitors that included determining the effects of using previously unexplored
core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro
bound to these inhibitors aided in compound design as well as shared structural features
among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this
novel set of inhibitors along with cytotoxicity studies provide new directions for
pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.
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