Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin

Abstract

Fluoroquinolones (FQs) are among the front-line antibiotics used to treat severe infections caused by Gram-negative bacteria. However, recently, due to toxicity concerns, their use has been severely restricted. Hence, efforts to direct delivery of this antibiotic specifically to bacteria/site of infection are underway. Here, we report a strategy that uses a bacterial enzyme for activation of a prodrug to generate the active antibiotic. The ciprofloxacin-latent fluorophore conjugate 1, which is designed as a substrate for nitroreductase (NTR), a bacterial enzyme, was synthesized. Upon activation by NTR, release of Ciprofloxacin (CIP) as well as a fluorescence reporter was observed. We provide evidence for the prodrug permeating bacteria to generate a fluorescent signal and we found no evidence for activation in mammalian cells supporting selectivity of activation within bacteria. As a testament to its efficacy, 1 was found to have potent bactericidal activity nearly identical to CIP and significantly reduced the bacterial burden in a neutropenic mouse thigh infection model, again, at comparable potency with CIP, a clinically used FQ. Thus, together, we have developed a small molecule that facilitates bacteria-specific fluoroquinolone delivery.

Fluoroquinolones’ Biological Activities against Laboratory Microbes and Cancer Cell Lines

“…As reported, norfloxacin was used as a positive control in the pipeline publications, including norfloxacin derivatives synthesis. Norfloxacin MIC against Gram-positive is presented in Table 3 [ 1 , 23 , 24 , 26 , 28 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. In brief, norfloxacin inhibitory activity against a panel of Gram-positive bacteria regardless of the strain varied relatively.…”

Synthesis of Cyclic Sulfite Diesters and their Evaluation as Sulfur Dioxide (SO2) Donors

“…reported sodium benzothiazole sulfonate as a water‐soluble SO 2 donor but with the limitation of a prolonged half‐life ( t 1/2 =13 d) at physiological pH 7.4 . Recently, SO 2 donors based on esterases, nitroreductases, thiols, and light as triggers, as well as on click chemistry as a mode of SO 2 donation, have been reported by our group and by the Singh and Wang groups (Scheme ). These strategies rely on the use of a cellular enzyme or a bio‐orthogonal reaction, and so can result in variable generation of sulfur dioxide depending on the availability of the stimulus.…”

Synthesis and Evaluation of Cyclic Sulfite Diesters as Sulfur Dioxide (SO2) Donors

“…[10] Xian et al reporteds odium benzothiazole sulfonate as aw ater-soluble SO 2 donor but with the limitation of ap rolongedh alf-life (t 1/2 = 13 d) at physiological pH 7.4. [11] Recently, SO 2 donors based on esterases, [8f, 12] nitroreductases, [13] thiols, [14] and light [15] as triggers, as well as on click chemistry as am ode of SO 2 donation, have been reported by our group and by the Singh and Wang groups (Scheme 1). These strategies rely on the use of ac ellular enzyme or ab io-orthogonal reaction, and so can result in variableg eneration of sulfur dioxide depending on the availability of the stimulus.T herefore, new self-immolative SO 2 donors that are stable at room temperature and permeate cellst oe nhance intracellular SO 2 levels could help better understanding of cellular responses to this important gaseous compound.…”