The physiological adaptations that permit growth and survival across environmental conditions are not yet well understood, particularly for extracytoplasmic processes. In the laboratory, the bacterium’s flexibility in growth requirements is reflected in robust proliferation across a wide range of temperature, salt, osmotic, pH, oxygenation, and nutrient conditions ( Ingraham and Marr, 1996). A commensal, pathogen, and environmental contaminant, Escherichia coli occupies and grows in diverse environmental niches, including the gastrointestinal tract, bladder, freshwater, and soil. The growth and survival of single-celled organisms relies on their ability to adapt to rapidly changing environmental conditions. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
This specialization may ensure robust growth and cell wall integrity in a wide range of conditions.Įditorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. Altogether, our findings reveal previously thought to be redundant enzymes are instead specialized for distinct environmental niches.
Genetic, biochemical, and cytological studies demonstrate that synthase activity is required for cell wall integrity across a wide pH range and influences pH-dependent changes in resistance to cell wall active antibiotics. Among these pH specialists are the class A penicillin binding proteins PBP1a and PBP1b defects in these enzymes attenuate growth in alkaline and acidic conditions, respectively. By modulating a single growth parameter-extracellular pH-we discovered a subset of these so-called ‘redundant’ enzymes in Escherichia coli are required for maximal fitness across pH environments. baumannii.Although the peptidoglycan cell wall is an essential structural and morphological feature of most bacterial cells, the extracytoplasmic enzymes involved in its synthesis are frequently dispensable under standard culture conditions. It showed that clinically-relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model.Ĭonclusions: This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. Sulbactam monotherapy was generally ineffective. 3–6 log 10 CFU/mL was observed with colistin monotherapy, followed by steady regrowth. In time-kill studies, rapid bacterial killing of ca. The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. All isolates possessed Acinetobacter-derived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenem-resistance gene bla OXA-23. Results: The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A.
In the dynamic studies, antibiotics were administered in various clinically-relevant dosing regimens that mimicked patient pharmacokinetics. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time-kill studies (three isolates). Methods: Whole genome sequencing was undertaken on eight carbapenem-resistant (colistin-susceptible) isolates of A. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. Aims: Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii ( A.