All authors read and approved the final manuscript “
“Backgr

All authors read and approved the final manuscript.”
“Background The emergence of antimicrobial resistance is severely limiting treatment options for many important infectious diseases [1, 2]. Traditionally the problem of antimicrobial resistance has been approached phosphatase inhibitor library by developing new compounds having increased potency. Unfortunately, development of new compounds is not keeping pace with the emergence of antibiotic-resistant pathogens. Consequently, new strategies are needed to preserve existing agents. One approach is to seek compounds that will enhance

the activity of distinct antimicrobial classes by blocking resistance mechanisms. For example, β-lactamase inhibitors extended the utility of β-lactams when delivered as combinations such as Augmentin (amoxicillin-clavulanic acid) [3], and inhibitors of efflux

pumps produced synergistic inhibition of growth against tetracycline-resistant Escherichia coli when used in combination with doxycycline [4]. The conventional strategy has been to identify genes whose inactivation increases the ability of compounds to block bacterial growth (decreases in minimal inhibitory concentration, MIC) [5]. Since some compounds kill bacteria by processes that are distinct from bacteriostatic action [6, 7] and since deficiencies in repair of lethal damage may not affect bacterial growth, the possibility CP-673451 order exists that genes involved in bacterial survival are distinct from those that protect from growth inhibition. Finding genes whose products protect from the lethal effects of stress requires screening procedures that differ from those used for bacteriostatic effects. In the present work, we used the prototype quinolone, nalidixic acid, as

a probe for screening genes whose products protect E. coli from lethal effects of stress. Nalidixic acid was chosen as the initial screening agent because bacteriostatic and lethal action are distinct events that are sensitive to different drug concentrations (for review see [8]). Mutants of E. coli, obtained by Tn5-mediated insertional mutagenesis, were screened for those that had the same bacteriostatic susceptibility to nalidixic acid as the wild-type strain Etomidate while exhibiting greater sensitivity to the lethal action of the drug. We call this new phenotype hyperlethality. With this phenotype we could eliminate from consideration mutants with altered drug uptake, efflux, and target interactions, since these properties affect bacteriostatic activity. The decreased survival of the mutants was expected in some cases to arise from disruption of genes involved in protecting from lethal stress. The hyperlethal mutants were then examined by measuring the lethal action of several other antimicrobial and environmental stresses. This work defined a novel bactericidal phenotype and identified a diverse set of poorly characterized bacterial stress-response genes as a new source of potential targets for antimicrobial enhancement.

Comments are closed.