Improper use of antibiotics has led to a great concern in the development of pathogenic microbial resistance. New Delhi metallo-β-lactamase 1 (NDM-1) producing bacteria are resistant to most of the β-lactam antibiotics, and so far, no new compounds have been clinically tested against these bacteria. In this study, ethanol extracts from the leaves of 240 medicinal plant species were screened for antibacterial activity against an NDM-1 Escherichia coli strain. The extracts that showed antibacterial activity were then tested for minimum inhibitory concentrations (MICs) and zones of inhibition. The extract from Combretum albidum G. Don, Hibiscus acetosella Welw. ex Hiern, Hibiscus cannabinus L., Hibiscus furcatus Willd., Punica granatum L., and Tamarindus indica L. showed bactericidal activity between 5 and 15 mg/ml and the MIC was between 2.56 and 5.12 mg/ml. All six plant extracts inhibited activity of the NDM-1 enzyme in vitro, and the IC50 value ranged between 0.50 and 1.2 ng/μl. Disruption of bacterial cell wall integrity by the plant extracts was clearly visible with scanning electron microscopy. Increases in membrane permeability caused 79.4–89.7% bacterial cell deaths as investigated by fluorescence-activated cell sorting. All the plant extracts showed synergistic effects when combined with colistin [fractional inhibitory concentration (ΣFIC) = 0.125–0.375], meropenem (ΣFIC = 0.09–0.313), and tetracycline (ΣFIC = 0.125–0.313). Thus, the plant extracts can be fractionated for the identification of active compounds, which could be used as new antibacterial compounds for the development of drugs against NDM-1 E. coli in addition to their use in combination therapy.
Gram-negative bacteria are notoriously more resistant to antibiotics than Gram-positive bacteria, primarily due to the presence of the outer membrane and a plethora of active efflux pumps. However, the potency of antibiotics also varies dramatically between different Gram-negative pathogens, suggesting major mechanistic differences in how antibiotics penetrate permeability barriers.
The clinical success of linezolid for treating Gram-positive
infections
paired with the high conservation of bacterial ribosomes predicts
that if oxazolidinones were engineered to accumulate in Gram-negative
bacteria, then this pharmacological class would find broad utility
in eradicating infections. Here, we report an investigative study
of a strategically designed library of oxazolidinones to determine
the effects of molecular structure on accumulation and biological
activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas
aeruginosa strains with varying degrees of compromise
(in efflux and outer membrane) were used to identify motifs that hinder
permeation across the outer membrane and/or enhance efflux susceptibility
broadly and specifically between species. The results illustrate that
small changes in molecular structure are enough to overcome the efflux
and/or permeation issues of this scaffold. Three oxazolidinone analogues
(3e, 8d, and 8o) were identified
that exhibit activity against all three pathogens assessed, a biological
profile not observed for linezolid.
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