Nature knows best: employing whole microbial strategies to tackle antibiotic resistant pathogens

The 2010s have seen a full recognition of the scourge of antimicrobial resistance (AMR) where antibioticresistance genes, many transferred from environmental bacteria, spread rapidly through hospital and farm populations of pathogens when selected for by applied antibiotics. Many of these resistance traits allow survival of bacteria in the very soil environments where other organisms naturally produce antibiotics. In a hospital or farm setting, they nullify the therapeutic effects of prescribed antibiotics. Along with this realization has come a return to natural environments to seek different new solutions. Although these settings are both the source of genes encoding the antibiotics we have relied upon and of the resistance genes that circumvent individual antibiotic agents or their actions, Nature offers much more than just that. Diverse molecular tactics are employed, between different micro-organisms, in natural environments, in a dazzling array of changing combinations to gain advantage in conflicts for territory and food. The war strategist in these processes is evolution and the armies and vigilantes are bacteria, bacteriophage, protozoa and fungi. The iChip, a novel method for growing previouslyunculturable bacteria, in their natural environment, developed by Kim Lewis and colleagues (Nichols et al., 2010) has been used to access untapped environmental bacteria for potential antibiotics (Ling et al., 2015). Indeed this may lead to the next generation of antibiotics that can be downstream processed into the pharmaceuticals of tomorrow, and combined with better stewardship may cause AMR to recede for future decades. In these new antibiotic discovery approaches, we humans pick up the individual weapons of micro-organisms, from their battlefields, and fire them ourselves, against pathogens. Certainly this will rearm humans to fight infection using the principles first applied by Fleming, Florey and Chain. Armed with advances in microscopy, 3rd generation sequencing technologies and greater understanding of the microbiota of different environments, we are now able to ask, more holistically, how do whole microorganisms kill each other? From this fundamental knowledge we will be able to employ them whole in the fight against AMR infection. The advantage of this is that multiple weapons may be used in a regulated way, by whole micro-organisms, against their foes. This more complex approach may be hard to resist by single gene mutations in the pathogens. Elegant microscopic studies by Melanie Blokesch and others (Borgeaud et al., 2015) studying the Type VI secretion apparatus have shown how environmental bacteria, such as Vibrio cholerae, use that system to stab and poison adjacent bacteria in a contact dependent manner wherein the killer senses the ‘prey’. The Type VI secretion apparatus shares conserved structures with the injective machinery of the larger bacteriophage viruses of bacteria. Using phage allows a multi-enzyme approach to bacterial killing but because a single receptor is often the portal of phage attack, selection for phage-resistant mutants is possible. On the plus side, given the enormous number and diversity of phage on earth, cocktails of assorted phage can be useful to delay the effect of such single genetic events (Merabishvili et al., 2009). Another, but very different, whole organism approach to bacterial killing, comes in the shape of predatory bacteria, including Bdellovibrio bacteriovorus. This invasive predatory bacterium enters and kills a wide range of Gram-negative bacteria and was, (akin to the discovery of penicillin by Alexander Fleming), isolated in an environmentally ‘infiltrated’ experiment that went unexpectedly. Stolp and Petzold isolated such predatory Bdellovibrio from plaques on a bacterial lawn in an experiment where they were studying phage. In fact, miniature predatory soil bacteria, too small to cause opacity were also able to invade and kill the larger bacteria on the lawn and produce plaques. (Stolp and Petzold, 1962; Stolp and Starr, 1963). Bacterial killing, by their predator ‘cousins’, does not rely on receptor binding, and so does not select for simple prey-resistance; but involves outer-membrane contacts and Type IV pilus activity for prey-invasion. Received 21 December, 2016; accepted 21 December, 2016. *For correspondence. E-mail liz.sockett@nottingham.ac.uk; Tel. (44)(0)115-8230325; Fax (44)-(0)115 823 0338.