The emergence and implications of metallo-β-lactamases in Gram-negative bacteria

The increase in Gram-negative broad-spectrum antibiotic resistance is worrisome, particularly as there are few, if any, "pipeline" antimicrobial agents possessing suitable activity against Pseudomonas spp. or Acinetobacter spp. The increase in resistance will be further enhanced by the acquisition of metallo-beta-lactamase (MBL) genes that can potentially confer broad-spectrum beta-lactam resistance. These genes encode enzymes that can hydrolyse all classes of beta-lactams and the activity of which cannot be neutralised by beta-lactamase inhibitors. MBL genes are often associated with aminoglycoside resistant genes and thus bacteria that possess MBL genes are often co-resistant to aminoglycosides, further compromising therapeutic regimes. Both types of genes can be found as gene cassettes carried by integrons that in turn are embedded within transposons providing a highly ambulatory genetic element. The dissemination of MBL genes is typified by the spread of bla(VIM-2), believed to originate from a Portuguese patient in 1995, and is now present in over 20 counties. The increase in international travel is likely to be a contributory factor for the ascendancy of mobile MBL genes as much as the mobility among individual bacteria. Fitness, acquisition and host dependency are key areas that need to be addressed to enhance our understanding of how antibiotic resistance spreads. There is also a pressing need for new, and hopefully novel, compounds active against pan-resistant Gram-negative bacteria - a growing problem that needs to be addressed by both government and industry.