![]() ![]() First, interference with human gene expression should be minimal, since there are no human homologues of antibiotic-resistance genes. Targeting specific antibiotic-resistance genes or their mRNA transcripts has advantages. These therapeutics would then be used adjunctively with already-approved antibiotics. 10, 18, 19Ī new strategy to combat antibiotic resistance is to design therapeutics that silence the expression of specific antibiotic-resistance genes. 13, 15, 16 Although β-lactamase inhibitors have been approved for combination use in humans, these are primarily effective for the serine (class A) and ampC (class C) β-lactamases, and none is effective against metallo-β-lactamases, including NDM-1. ![]() 13–17 NDM-1 is particularly dangerous because it confers resistance to some of our most potent antibiotics, the carbapenems, and is accompanied by genes encoding resistance to most, if not all, classes of available antibiotics. ![]() 13 Subsequently, NDM-1-associated resistance has rapidly spread in a clonal fashion throughout the world at an alarming rate to many Gram-negative pathogens, including Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii. It was first identified in 2008 in a strain of Klebsiella pneumoniae isolated from a patient in Sweden who had acquired the bacterium in India. The New Delhi metallo-β-lactamase (NDM-1) is a plasmid-associated Ambler class B β-lactamase. 2–9 This problem is confounded by a lack of development and approval of new classes of antibiotics in the last three decades. From 2001 to 2012, acute-care hospitals reporting at least one healthcare-associated infection from a carbapenem-resistant Enterobacteriaceae (CRE) increased from 1.2% to 4.6% 1 and the mortality rate from a CRE infection is estimated to be between 40% and 50%. Many strains of bacterial pathogens have become resistant to multiple antibiotics, and some are now resistant to all standard antibiotics, making treatment challenging. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.Ĭonclusions: These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem-resistant infections in multiple genera of Gram-negative pathogens.Īntibiotic resistance is an escalating, worldwide problem that has gained urgency in the past decade. Results: In vitro, the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo. Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene. Objectives: The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). ![]()
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