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Alorabi, M.

Publications and source records attributed to Alorabi, M..

2 recordsLinked to original sources
bioRxiv2020

Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamase by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting.

Meropenem is a clinically important antibacterial reserved for treatment of multi-resistant infections. In meropenem-resistant bacteria of the family Enterobacteriales, NDM-1 is considerably more common than IMP-1, despite both metallo-{beta}-lactamases (MBLs) hydrolysing meropenem with almost identical kinetics. We show that blaNDM-1 consistently confers meropenem resistance in wild-type Enterobacteriales, but blaIMP-1 does not. The reason is higher blaNDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of blaNDM-1 positive Enterobacteriales because of amino acid starvation. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded blaNDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same blaNDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation, reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.

microbiology↗
bioRxiv2018

Synonymous lysine codon usage modification in a mobile antibiotic resistance gene similarly alters protein production in bacterial species with divergent lysine codon usage biases because it removes a duplicate AAA lysine codon.

The mobile antibiotic resistance gene blaIMP-1 is clinically important and has a synonymous AAA:AAG lysine codon usage bias of 73:27. This bias is like that seen in experimentally determined highly expressed genes in Escherichia coli and Acinetobacter baumanii, but quite different from that seen in Pseudomonas aeruginosa (26:74 AAA:AAG). Here we show that, paradoxically, shifting the AAA:AAG lysine codon bias to 8:92 in blaIMP-1 expressed from a natural promoter results in significantly more IMP-1 production in all three species. Sequential site directed mutagenesis revealed that increased IMP-1 production occurs following removal of an AAA,AAA double lysine codon and that otherwise, lysine codon usage had no observable impact on IMP-1 production. We conclude that ribosomal slippage at this poly-adenosine region reduces efficient translation of IMP-1 and that punctuating the region with guanine reduces ribosomal slippage and increases IMP-1 production.

microbiology↗