Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase that inactivates a broad range of rifamycin antibiotics. Our findings describe a mechanism of rifamycin inactivation initiated by monooxygenation of the 2-position of the naphthyl group, which subsequently results in ring opening and linearization of the antibiotic. The result is an antibiotic that no longer adopts the basket-like structure essential for binding to the RNA exit tunnel of the target RpoB, thereby providing the molecular logic of resistance. This unique mechanism of enzymatic inactivation underpins the broad spectrum of rifamycin resistance mediated by Rox enzymes and presents a new antibiotic resistance mechanism not yet seen in microbial antibiotic detoxification.

RATIONALE: Panic disorder (PD) has been shown to be associated with worse asthma outcomes in individuals with asthma, but the psychophysiological mechanisms underlying this association remain unclear. Some theories suggest that asthmatics with PD have worse underlying asthma severity and some argue that they simply report more symptoms based on their tendency to catastrophize bodily sensations. METHODS: A total of 39 patients (19 with and 20 without PD) with physician-diagnosed asthma underwent standard metacholine challenge testing (MCT). Demographic and medical/asthma history information was collected at baseline. Pre and post MCT patients completed the Panic symptom scale (PSS), the Modified Borg Scale (MBS), and the Subjective distress visual analogue scale (SD-VAS). Heart rate (HR), systolic, and diastolic blood pressure (SBP/DBP) were recorded pre, during, and post MCT. RESULTS: There were no differences in PC20 values between asthmatics with and without PD (F=0.21, p=0.652). PD patients had a higher number of panic symptoms (from the PSS) at post-test compared to those without PD ([M (SD)] PD pre = 2.21 (2.42), PD post = 5.00 (3.32); non-PD pre = 0.75 (1.07), non-PD post = 2.25 (1.89): F=5.05, p=0.031). There were no differences in MBS (F=0.70, p=0.407), SD-VAS anxiety (F=0.36, p=0.554), SD-VAS worry (F=0.84, p=0.366), HR (F=0.06, p=0.805), SBP (F=0.49, p=0.487), or DBP (F=0.01, p=0.942) between PD and non-PD patients. CONCLUSIONS: Results suggest that having PD is associated with increased subjective responses during MCT, with no impact on objective measures of asthma. Future research should focus on the potential impact of these increased panic attack-like symptoms on long-term asthma care and if intervening on them influences outcomes such as emergency room visits. Financial Support: SLB and KLL were supported by CIHR and FRQS salary awards.