Some Staphylococcus aureus bacteria are thought to survive standard antibiotic treatment by 'hiding' in host cells. But an antibody–antibiotic conjugate has been developed that targets these bacteria in mouse models. See Article p.323
The pathogenic bacterium Staphylococcus aureus causes thousands of deaths each year. Therapy is sometimes unsuccessful, partly because antibiotic-resistance genes are spreading worldwide. However, even strains of S. aureus that lack resistance genes are often difficult to kill with available antibiotics; it has been suggested that the bacteria 'hide' inside host cells. This hypothesis inspired Lehar et al.1 who, on page 323 of this issue, present a construct in which an antibiotic is linked to an antibody that binds to the pathogen's surface. Alone, this 'prodrug' is inactive, but when prodrug-coated bacteria enter host cells, enzymatic activity releases the antibiotic. In mouse models of S. aureus infection, this strategy was strikingly more potent than standard antibiotic treatment.
Antibiotics are a pillar of modern medicine, but they are not effective in all cases. There are at least three explanations for this. First, important pathogenic bacteria, including many S. aureus strains, have acquired resistance against standard antibiotics2. Second, the pathogen may hide in host sites that cannot be reached by antibiotic molecules, or where the environmental conditions, such as high acidity, render the antibiotics inactive. And third, in certain circumstances, bacteria can switch to a 'persistent' lifestyle that makes them insensitive to antibiotics3. The switch to persistence is still not completely understood but can occur in some pathogens when they enter host cells.
In S. aureus, a range of virulence factors manipulate host-cell processes, prohibit efficient immune responses and fuel infections in wounds, the bloodstream and other sites. In the absence of antibiotic-resistance genes, several different classes of antibiotic are used to treat S. aureus infections; rifampicin antibiotics are sometimes employed to target intracellular reservoirs of the bacterium. However, these classic antibiotics are often unable to cure the infection.
Lehar and colleagues speculated that this failure is due to either insufficient accessibility of the antibiotic or insufficient activity against intracellular S. aureus. In an attempt to overcome these problems, the researchers first generated a rifampicin derivative (a 'rifalogue') with altered physicochemical properties that gives superior activity against S. aureus cells that have switched to a persistent lifestyle. Next, they identified an antibody that tightly binds to sugar structures found on the surface of all S. aureus strains tested. Then they covalently joined these two components by using a chemical bridge that can be broken by protease enzymes that are present at the intracellular sites where S. aureus is thought to hide out (Fig. 1). Strikingly, in a mouse infection model, this antibody–antibiotic conjugate (AAC) was much more effective at reducing pathogen loads than two conventional antibiotics currently used to treat recalcitrant S. aureus infections.
This approach is reminiscent of antibody-targeted prodrug strategies that are currently used in cancer therapy4, and these proof-of-principle data suggest that targeted antibiotic delivery is a promising strategy for fighting obstinate intracellular pathogens. It remains to be seen whether AACs are as efficient at treating bacterial infections in humans as they are in mice, especially in chronically infected patients, who often already have antibodies against S. aureus. Such antibodies may shield the bacterial surface from AAC binding, and therefore interfere with the targeting of the prodrug. Moreover, because the antibiotic makes up only around 1% (by mass) of the current construct, the AAC would have to be applied at the equivalent of more than a gram per dose for an adult human patient. This might be improved in the future by replacing the antibody with smaller surface-targeting entities.
Why is the AAC approach so much more effective than standard antibiotics? One reason is that the rifalogue is more efficient than rifampicin at killing persistent S. aureus cells. Another is that the kinetics of drug distribution, excretion and inactivation seem to be favourably affected by its fusion to the antibody. Coating bacterial cells with the antibody-bound prodrug may also steer the bacteria to be taken up into intracellular compartments (lysosomes) that have high levels of the enzymes needed to release the antibiotic5. And accumulation of the AAC on the pathogen's surface may cause particularly high local concentrations of the bacteria in the intracellular hideout. It remains to be seen which of these mechanisms account for the in vivo potency of the AAC.
Compared with conventional antibiotic therapy, the prodrug approach is likely to reduce both the emergence of antibiotic resistance (by reducing the exposure of other bacteria to the active drug) and the disruption of the body's normal communities of microorganisms. There is still plenty of scope for optimizing the targeting moieties and the chemical bridges6. Moreover, the strategy may allow researchers to revisit older antimicrobials that were not developed for therapy because they had unfavourable pharmacokinetics or toxicity. The AAC approach could also expand our arsenal against other notorious intracellular pathogens, such as Mycobacterium tuberculosis.
Alternative strategies to tackle the growing problem of antibiotic resistance are also emerging. These include antibiotics that specifically target persistent cells7, agents that stimulate the host's antimicrobial defences to augment antibiotic therapy8,9, or harmless 'biocontrol' agents that colonize the host and inhibit pathogen growth10. We can hope that such approaches, alongside the AAC strategy presented by Lehar et al., will boost our capacity to treat bacterial infections. Footnote 1
Lehar, S. M. et al. Nature 527, 323–328 (2015).
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Lewis, K. Annu. Rev. Microbiol. 64, 357–372 (2010).
Giang, I., Boland, E. L. & Poon, G. M. K. AAPS J. 16, 899–913 (2014).
Joller, N. et al. Proc. Natl Acad. Sci. USA 107, 20441–20446 (2010).
Yacoby, I. & Benhar, I. Infect. Disord. Drug Targets 7, 221–229 (2007).
Conlon, B. P. et al. Nature 503, 365–370 (2013).
Kaiser, P. et al. PLoS Biol. 12, e1001793 (2014).
Porte, R. et al. Antimicrob. Agents Chemother. 59, 6064–6072 (2015).
Iwase, T. et al. Nature 465, 346–349 (2010).
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