Competition Studies Confirm Two Major Barriers That
Can Preclude the Spread of Resistance to Quorum-Sensing Inhibitors
in Bacteria
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Abstract
The growing threat of antibiotic
resistance necessitates the development
of novel antimicrobial therapies. Antivirulence agents that target
group-beneficial traits in microorganisms (i.e., phenotypes that help
the cells surrounding the producer cell instead of selfishly benefiting
only the producer cell) represent a new antimicrobial approach that
may be robust against the spread of resistant mutants. One prominent
group-beneficial antivirulence target in bacteria is quorum sensing
(QS). While scientists are producing new QS inhibitors (QSIs) at an
increasing pace for use as research tools and potential therapeutic
leads, substantial work remains in empirically demonstrating a robustness
against resistance. Herein we report the results of <i>in vitro</i> competition studies in <i>Pseudomonas aeruginosa</i> that
explicitly confirm that <i>two separate barriers</i> can
impede the spread of resistance to QSIs: (1) insufficient native QS
signal levels prevent rare QSI-resistant bacteria from expressing
their QS regulon, and (2) group-beneficial QS-regulated phenotypes
produced by resistant bacteria are susceptible to cheating by QSI-sensitive
neighbors, even when grown on a solid substrate with limited mixing
to mimic infected tissue. These results underscore the promise of
QSIs and other antivirulence molecules that target group beneficial
traits as resistance-robust antimicrobial treatments and provide support
for their further development