N-acylhomoserine lactones, better known as AHLs, are the quorum-sensing molecules that Gram-negative bacteria use to coordinate cell-density-dependent processes, which include virulence, biofilm formation and antibiotic synthesis. A new study published in Proceedings of the National Academy of Sciences USA shows that these versatile molecules can also function as antimicrobials.

Studying the coordinated light production of the glowing bacterial symbionts that populate the light organ of the squid led to a realization that Gram-negative bacteria use diffusible signalling molecules to coordinate population behaviour and behave as multicellular groups. These signalling molecules, named quorum-sensing hormones or quormones, are produced by many Gram-negative bacteria. Intense research in the past 10 years has led to the elucidation of quormone biosynthetic pathways and an understanding of the regulatory functions of quormones.

AHLs, one class of quormone, are produced by several important Gram-negative animal and plant pathogens, including Pseudomonas aeruginosa, which can infect cystic fibrosis sufferers to cause debilitating opportunistic infections. While investigating how long AHLs can persist in an aqueous environment, Kaufmann et al. discovered that one of the AHLs produced by P. aeruginosa, N-(3-oxododecanoyl) homoserine lactone, was non-enzymatically and spontaneously converted into a tetramic acid. Importantly, this wasn't a peculiarity of N-(3-oxododecanoyl) homoserine lactone, and tetramic acids were produced by a selection of variant chain-length AHLs that Kaufmann et al. tested.

Using bioassays, the tetramic acid produced was shown to be cytotoxic — at concentrations that would be present in biofilms formed by P. aeruginosa — but only towards Gram-positive bacteria, including Bacillus, Streptococcus and Listeria species. Surprisingly, N-(3-oxododecanoyl) homoserine lactone was also mildly cytotoxic towards some of the Gram-positive strains tested. Both the AHL and the tetramic acid are much less potent than other antimicrobials in clinical use, but, nonetheless, their activity might give the producer organism a competitive advantage in a mixed community.

Tetramic acids also bind metals, although the effects of metal chelation on their cell-killing functions are variable. The AHL-derived tetramic acid identified in this study chelated Fe3+, and although the tetramic acid didn't bind the metal as tightly as pyoverdin, the main siderophore of P. aeruginosa, it had higher affinity for iron than pyochelin, a second siderophore found in this species, so tetramic acid might function both as an iron scavenger and as an antimicrobial.

These interesting observations need to be related to the behaviour of AHL-producing bacteria in mixed communities, but it seems that when a quorum is reached, the signals that are produced might regulate multiple phenotypes and allow Gram-negative producer species to gain a competitive advantage in communities.