Small Molecule Suppression of Carbapenem Resistance in NDM-1 Producing Klebsiella pneumoniae

Abstract

The already considerable global public health threat of multi-drug resistant Gram-negative bacteria has become even more of a concern following the emergence of New-Delhi metallo-β-lactamase (NDM-1) producing strains of Klebsiella pneumoniae and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of K. pneumoniae to imipenem and meropenem, in addition to suppressing resistance of other β-lactam non-susceptible K. pneumoniae strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold while exhibiting little bactericidal activity itself.

Combination approaches to combat multidrug-resistant bacteria

“…A number of 2-aminoimidazole containing compounds derived from the marine natural products oroidin and bromoageliferin have been reported to suppress resistance of both Gram positive 40 and Gram-negative 40a, 41 bacteria to β-lactam antibiotics (Figure 2b–c). The compound in Figure 2b suppressed resistance of a New Delhi metallo-β-lactamase (NDM-1) producing strain of K. pneumoniae to carbapenem antibiotics, lowering MICs by 16-fold.…”

Potentiation of the fosmidomycin analogue FR 900098 with substituted 2-oxazolines against Francisella novicida

“…Surprisingly, the previously synthesized 2-aminoimidazole ( 10 ) analogue actually increased the MIC to 32 μg mL −1 , which has previously been shown to lower the MIC of β-lactam antibiotics and colistin against other gram-negative bacteria. 28 …”

Potent Small‐Molecule Suppression of Oxacillin Resistance in Methicillin‐Resistant Staphylococcus aureus

“…An inactive compound ( 7e ) was found to be com-parable, with 83%, 24%, 23%, and 16% of cells damaged at 4x, 1x, 0.4x, and 0.25x the MIC respectively, suggesting that cell membrane permeabilization is not the mechanism by which compound 7d suppresses resistance to oxacillin. Importantly for a potential antibiotic adjuvant, 7d exhibited little effect on eukaryotic cell membranes, as determined by measuring the hemolytic activity against mechanically difibrinated sheep blood [9] . At its active resistance suppression concentration (5 µM), less than 1% lysis was observed compared to triton×positive control, while only 5.6% lysis was observed as high as 50 µM.…”