Monday, 7 July 2014

Aspergillus Metabolite Overcomes Antibiotic Resistance

It is well documented that shortly after the arrival of antibiotics came the response from bacteria - antibiotic resistance that renders the original antibiotics useless. There are several mechanisms that bacteria can use to become resistant and one of the major systems used is to produce enzymes (β-lactamases) that directly attack the chemical structure of some antibiotics, destroying them.

It is clear that we need to keep resistance under control and there have been several strategies to manage this resistance including limiting the use of antibiotics, better prevention of infection and encouraging the patient to use the full course of prescribed antibiotic.

These strategies have only been partly effective and there is an ever more urgent need to provide new antibiotics - a fact that is being recognised by our political leaders recently.

Happily there are other ways to defeat resistance and this research group working in Ontario, Canada & Cardiff, Wales have exploited one such alternative by rendering what were resistant bacteria sensitive to antibiotics once more by inhibiting the β-lactamase activity.

Quoting from their paper:
The β-lactams (penicillins, cephalosporins, carbapenems and monobactams) are one of the most important and frequently used classes of antibiotics in medicine and are essential in the treatment of serious Gram-negative infections.
Since the clinical introduction of penicillins and cephalosporins over 60 years ago, the emergence of β-lactamases, enzymes that hydrolyse the β-lactam ring that is essential for the cell-killing activity of the antibiotics, has been an ongoing clinical problem1.
Antibiotic resistance has intensified medicinal chemistry efforts to broaden antibacterial spectrum while shielding the core β-lactam scaffold from β-lactamase-catalysed hydrolysis. The result has been multiple generations of β-lactams with improved efficacy and tolerance to existing β-lactamases. However, pathogenic bacteria have in turn evolved further resistance mechanisms primarily by acquiring new or modified β-lactamases. This is typified by the emergence of extended spectrum β-lactamases that inactivate many of the latest generation cephalosporins and penicillins (but not carbapenems)2.
Consequently, the past two decades have seen substantial increases in the utilization of carbapenems such as imipenem and meropenem. Predictably, this increase in carbapenem consumption has been accompanied by the emergence of carbapenem-resistant Gram-negative pathogens (CRGNP)3, 4. In particular, carbapenem-resistant Enterobacteriaceae (CRE) is a growing crisis across the globe5 as witnessed by recent outbreaks in Chicago6 and British Columbia7.
The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found.
Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.
NOTE: Aspergillomarasmine is a natural product of Aspergillus oryzae. This is one more example of fungi providing help in our battles against bacterial infection.

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