Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of N-aryl-2nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (e.g., HP 29, against methicillin-resistant Staphylococcus aureus: MIC = 0.075 μM; MBEC = 2.35 μM), and transcriptional analysis revealed that HPs 3, 28, and 29 induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against Mycobacterium tuberculosis (HP 34, MIC = 0.80 μM against CDC1551). This work established new SAR insights, and HP 29 demonstrated efficacy in dorsal wound infection models in mice. Encouraged by these findings, we believe that HPs could lead to significant advances in the treatment of challenging infections.
Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common causes of bacterial keratitis and corresponding corneal blindness. Accordingly, such infections are predominantly treated with broad-spectrum fluoroquinolones, such as moxifloxacin. Yet, the rising fluoroquinolone resistance has necessitated the development of alternative therapeutic options. Herein, we describe the development of a polymyxin B-trimethoprim (PT) ophthalmic formulation containing the antibiotic rifampin, which exhibits synergistic antimicrobial activity toward a panel of contemporary ocular clinical S. aureus and P. aeruginosa isolates, low spontaneous resistance frequency, and in vitro bactericidal kinetics and antibiofilm activities equaling or exceeding the antimicrobial properties of moxifloxacin. The PT plus rifampin combination also demonstrated increased efficacy in comparison to those of either commercial PT or moxifloxacin in a murine keratitis model of infection, resulting in bacterial clearance of 70% in the animals treated. These results suggest that the combination of PT and rifampin may represent a novel antimicrobial agent in the treatment of bacterial keratitis.
Bacterial keratitis causes significant blindness, yet antimicrobial resistance has rendered current treatments ineffective. Polymyxin B-trimethoprim (PT) plus rifampin has potent in vitro activity against Staphylococcus aureus and Pseudomonas aeruginosa, two important causes of keratitis. Here we further characterize this combination against P. aeruginosa in a murine keratitis model. PT plus rifampin performed comparably to or better than moxifloxacin, the gold standard, suggesting that the combination may be a promising therapy for bacterial keratitis.
Hand sanitizers have been developed as a convenient means to decontaminate an individual’s hands of bacterial pathogens in situations in which soap and water are not available. Yet to our knowledge, no study has compared the antibacterial efficacy of a large collection of hand sanitizers. Using zone of growth inhibition and kill curve assays, we assessed the performance of 46 commercially available hand sanitizers that were obtained from national chain big-box stores, gasoline stations, pharmacies, and boutiques for antibacterial activity toward prototypical Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacterial pathogens. Results revealed substantial variability in the efficacy of many sanitizers evaluated. Formulations following World Health Organization-recommended ingredients (80% ethanol or 75% isopropyl alcohol) or those including benzalkonium chloride as the active principal ingredient displayed excellent antibacterial activity, whereas others exhibited modest or poor activity in the assays performed. Results also revealed that E. coli was generally more susceptible to most sanitizers in comparison to S. aureus and that there was significant strain-to-strain variability in hand sanitizer antimicrobial efficacy regardless of the organism evaluated. Further, tests of a subset of hand sanitizers toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed no direct correlation between antibacterial and antiviral performance, with all ethyl alcohol formulations performing equally well and displaying improved activity in comparison to benzalkonium chloride-containing sanitizer. Taken together, these results indicate that there is likely to be substantial variability in the antimicrobial performance of commercially available hand sanitizers, particularly toward bacterial pathogens, and a need to evaluate the efficacy of sanitizers under development. IMPORTANCE In response to the coronavirus disease 2019 (COVID-19) pandemic, hand hygiene has taken on a prominent role in efforts to mitigate SARS-CoV-2 transmission and infection, which has led to a radical increase in the number and types of hand sanitizers manufactured to meet public demand. To our knowledge, no studies have evaluated or compared the antimicrobial performance of hand sanitizers that are being produced under COVID-19 emergency authorization. Tests of 46 commercially available hand sanitizers purchased from national chain brick-and-mortar stores revealed considerable variability in their antibacterial performance toward two bacterial pathogens of immediate health care concern, S. aureus and E. coli. Expanded testing of a subset of hand sanitizers revealed no direct correlation between antibacterial performance of individual sanitizers and their activity toward SARS-CoV-2. These results indicate that as the pandemic subsides, there will be a need to validate the antimicrobial efficacy of sanitizers being produced.
Purpose: Staphylococcus aureus is a leading cause of keratitis requiring urgent antimicrobial treatment. However, rising antibiotic resistance has rendered current ophthalmic antibiotics increasingly ineffective. First, a diverse, ocular S. aureus strain set was evaluated for resistance to six commonly used ophthalmic antibiotics. Next, a recently discovered antimicrobial drug combination containing polymyxin B/trimethoprim + rifampin that displayed impressive efficacy towards S. aureus in both in vitro and in vivo studies was evaluated as a potential novel keratitis therapeutic through testing this combination's efficacy against the clinical strain set.Methods: 163 S. aureus isolates were collected commercially or from the University of Rochester, Flaum Eye Institute. The minimum inhibitory concentrations (MICs) of moxifloxacin, levofloxacin, vancomycin, erythromycin, tobramycin, rifampin and polymyxin B/trimethoprim (PT) were determined for the entire strain set to establish the incidence of resistance to current treatment options among a contemporary clinical isolate set and compared to the performance of PT + rifampin.Results: Among all 163 isolates tested, high rates of antibiotic resistance were found toward erythromycin (69% resistance), moxifloxacin (33%), levofloxacin (40%) and tobramycin (17%). Conversely, the entire strain set, including multi-drug resistant (MDR) isolates, was sensitive to PT + rifampin, demonstrating the potency of this combination. Conclusions:We establish that antibiotic resistance is pervasive among clinical S. aureus isolates, underscoring the concern for the effectiveness of current ophthalmic antibiotics. The drug combination of PT + rifampin, however, eradicated 100% of isolates tested, demonstrating the
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