Aspergillomarasmina A

Anche su questo blog (https://ilblogdellasci.wordpress.com/2012/12/18/una-pallottola-spuntata/) abbiamo segnalato il problema della crescita mondiale della resistenza agli antibiotici con lo sviluppo (specie in ambito ospedaliero) di batteri che sono resistenti a tutti gli antibiotici conosciuti; per questo motivo l’OMS ha recentemente pubblicato uno studio dedicato al problema (http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1) arrivando a parlare di era post-antibiotica.

Un articolo pubblicato su Nature di questa settimana apre uno spiraglio con la scoperta che una sostanza, conosciuta da oltre 50anni ed estraibile da Aspergillus Versicolor, possiede una potente attività di inibizione di quegli enzimi batterici, le cosiddette beta-lattamasi che distruggono gli antibiotici; in particolare la sostanza, aspergillomarasmina A peso molecolare poco più di 300 inibisce sia le lattamasi NDM-1 che VIM in vivo e in vitro ed è ben tollerata. Si apre quindi la possibilità che l’associazione dei comuni antibiotici con sostanze come questa possano restaurare l’efficacia degli antibiotici e che stavolta gli uomini siano più saggi nell’usare di questa possibilità.

Da Nature di questa settimana.

Infection with Gram-negative pathogens bearing metallo-β-lactamases such as NDM-1 and VIM is a growing public health problem and threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. Here, Gerard Wright and colleagues report a screen for naturally produced inhibitors of NDM-1 in an extensive collection of DMSO-dissolved natural product extracts derived from environmental microorganisms. One extract (from Aspergillus versicolor) exhibited a particularly potent anti-NDM-1 activity and was identified as aspergillomarasmine A (AMA), a natural product first reported some 50 years ago associated with leaf wilting. AMA is a rapid and potent inhibitor of both NDM-1 and VIM-2, and the authors find that AMA fully restores antibiotic efficacy in vitro and in vivo against bacterial pathogens possessing either VIM- or NDM-type resistance genes. AMA is non-toxic and well tolerated, making it a realistic prospect as an antibiotic adjuvant.

Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance
•    Andrew M. King,
•    Sarah A. Reid-Yu,
•    Wenliang Wang,
•    Dustin T. King,
•    Gianfranco De Pascale,
•    Natalie C. Strynadka,
•    Timothy R. Walsh,
•    Brian K. Coombes
•    & Gerard D. Wright
Nature 510, 503–506 (26 June 2014)
doi:10.1038/nature13445

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. 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.

(cdv)