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One of the challenges associated with the treatment of Pseudomonas aeruginosa infections is the high prevalence of multidrug resistance (MDR). Since conventional antibiotics are ineffective at treating such bacterial infections, innovative antibiotics acting upon novel targets or via mechanisms are urgently required. In this study, we identified a quorum sensing inhibitor (QSI), norharmane, that uniquely shows weak antibacterial activity but strongly inhibits pyocyanin production and biofilm formation of MDR P. aeruginosa. Biophysical experiments and molecular docking studies showed that norharmane competes with anthraniloyl-AMP for anthranilyl-CoA synthetase PqsA of P. aeruginosa at the ligand-binding pocket, which is not exploited by current inhibitors, thereby altering transcription regulatory activity. Moreover, norharmane exhibits synergy with polymyxin B. This synergism exhibits a high killing rate, low probability of resistance selection, and minimal cytotoxicity. Notably, norharmane can effectively boost polymyxin B activity against MDR P. aeruginosa-associated infections in animal models. Together, our findings provide novel insight critical to the design of improved PqsA inhibitors, and an effective combination strategy to overcome multiantibiotic bacterial resistance using conventional antibiotics and QSIs. IMPORTANCE Pseudomonas aeruginosa is a dominant hospital-acquired bacterial pathogen typically found in immunocompromised individuals. It is particularly dangerous for patients with chronic lung diseases and was identified as a serious threat for patients in the 2019 Antimicrobial Resistance Threats report (https://www.cdc.gov/drugresistance/biggest-threats.html). In this study, we used activity-based high-throughput screening to identify norharmane, a potent and selective inhibitor of P. aeruginosa PqsA, which is a well-conserved master quorum sensing (QS) regulator in multidrug resistant (MDR) P. aeruginosa. This compound competitively binds anthranilyl-CoA synthetase PqsA at the anthraniloyl-AMP binding domain, which has not been exploited by known inhibitors. Remarkably, norharmane can significantly block the production of the virulence factor, pyocyanin (87%), and biofilm formation (80%) in MDR P. aeruginosa. Furthermore, norharmane is capable of augmenting polymyxin B activity against MDR P. aeruginosa in cell cultures and animal models. Taken together, these results suggest that norharmane may be an effective adjuvant for combating multiantibiotic bacterial resistance.

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Clostridioides difficile infection is one of the leading causes of antibiotic-associated infectious diarrhea, and is associated with increased incidence and severity worldwide. While antibiotics have traditionally been used for prophylaxis and treatment of C. difficile infection, elevated antibiotic resistance has promoted the development and spread of C. difficile infection. Since the current standard-of-care antibiotics are ineffective for treating infections, there is an urgent need for novel antibacterial drugs or strategies to target C. difficile infection. C. difficile virulence and vital physiological functions are considered to be ideal targets. Thus, several promising lead compounds have been identified through screening both synthetic and natural product libraries. The goal of this review is to provide an update of the current scientific knowledge of C. difficile infection, focusing on small molecule inhibitors, which can effectively inhibit C. difficile by suppressing virulence or destroying vital physiological structures.

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BACKGROUND: Incidence of skin pigmentation disorders has been on the rise globally. This calls for safer and more effective topical skin lightening and freckle-removing products. In this study, we hypothesized that Soluble Pearl Extract (SPE) may possess endothelin antagonizing compounds with good skin whitening effects. OBJECTIVES: (a) To determine the effect and mechanisms of SPE on ET-1-treated B16 melanoma cells. (b) To explore the cytotoxic effects of SPE on B16 melanoma cells. METHODS: CCK-8 assay was performed to determine how SPE and ET-1 affect the proliferation rate of B16 melanoma cells, the NaOH lysis assay was conducted to quantify the content of melanin while the tyrosinase activity was determined by DOPA oxidation test. The mRNA and protein expression levels of TYR and TRP-1 were determined by qRT-PCR assay and Western blot assay, respectively. RESULTS: We found that SPE at 0.1 and 1 µg/mL concentrations has no effect on the proliferation of the cells and 10 nmol/L ET-1 promoted B16 melanoma cells proliferation. Notably, B16 melanoma cells treated with 10 nmol/L ET-1 exhibited significantly higher melanin synthesis, tyrosinase activity, TYR, and TRP-1 mRNA expression levels compared with untreated cells. Of note, the effects of 10 nmol/L ET-1 treatment were abolished with SPE in a dose-dependent manner. CONCLUSIONS: SPE inhibits endothelin thereby safely and effectively lightening lightens the skin by antagonizing endothelin. Moreover, SPE is safe and effective.

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Vibrio harveyi is a marine bacterial pathogen which infects a wide range of marine organisms and results in severe loss. Antibiotics have been used for prophylaxis and treatment of V. harveyi infection. However, antibiotic resistance is a major public health threat to both human and animals. Therefore, there is an urgent need for novel antimicrobial agents with new modes of action. In V. harveyi, many virulence factors production and bioluminescence formation depend on its quorum sensing (QS) network. Therefore, the QS system has been widely investigated as an effective potential target for the treatment of V. harveyi infection. This perspective focuses on the quorum sensing inhibitors (QSIs) of V. harveyi QS systems (LuxM/N, LuxS/PQ, and CqsA/S) and evaluates medicinal chemistry strategies.

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The quinolactacins are a family of pyrroloquinoline-type natural products from Penicillium sp. From the organic extract of Penicillium sp. ENP701 fermentation broth, a microorganism from the east China sea, one new quinolactacin was isolated and named quinolactacin-H. The structure of quinolactacin-H was determined by spectroscopic analysis and the absolute configurations by X-ray crystallographic analysis. Enantioselective total synthesis of (R)-(+)-quinolactacin-H and (S)-(-)-quinolactacin-H was achieved. When assayed through crystal violet (CV) microtiter plate biofilm, both (R) and (S)-quinolactacin-H showed a strong inhibition and dispersion of Pseudomonas aeruginosa PAO1 biofilms. Thus, quinolactacins could be proposed and developed as natural anti-bioflm agents in order to solve the problem of microbial resistance in future.

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Microbial siderophores are multidentate Fe(III) chelators used by microbes during siderophore-mediated assimilation. They possess high affinity and selectivity for Fe(III). Among them, marine siderophore-mediated microbial iron uptake allows marine microbes to proliferate and survive in the iron-deficient marine environments. Due to their unique iron(III)-chelating properties, delivery system, structural diversity, and therapeutic potential, marine microbial siderophores have great potential for further development of various drug conjugates for antibiotic-resistant bacteria therapy or as a target for inhibiting siderophore virulence factors to develop novel broad-spectrum antibiotics. This review covers siderophores derived from marine microbes.

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Quorum sensing inhibitors (QSIs) present a promising alternative or potent adjuvants of conventional antibiotics for the treatment of antibiotic-resistant bacterial strains, since they could disrupt bacterial pathogenicity without imposing selective pressure involved in antibacterial treatments. This review covers a series of molecules showing quorum sensing (QS) inhibitory activity that are isolated from marine microorganisms, including bacteria, actinomycetes and fungi, and chemically synthesized based on QSIs derived from marine microorganisms. This is the first comprehensive overview of QSIs derived from marine microorganisms and their synthetic analogues with QS inhibitory activity.

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PURPOSE: The aim of this study was to evaluate the outcome of a minimally invasive surgical technique for the treatment of patients with acromioclavicular joint dislocation. METHODS: Sixteen patients with complete acromioclavicular joint dislocation were enrolled in this study. All patients were asked to follow the less active rehabilitation protocol post-operatively. Computed tomography with 3-D reconstruction of the injured shoulder was performed on each patient post operatively for the assessment of the accuracy of the suture anchor placement in the coracoid process and the reduction of the acromioclavicular joint. Radiographs of Zanca view and axillary view of both shoulders were taken for evaluating the maintenance of the acromioclavicular joint reduction at each follow-up visit. The Constant shoulder score was used for function assessment at the final follow-up. RESULTS: Twenty seven of the 32 anchors implanted in the coracoid process met the criteria of good position. One patient developed complete loss of reduction and another had partial loss of reduction in the anteroposterior plane. For the other 14 patients, the mean Constant score was 90 (range, 82-95). For the patients with partial and complete loss of reduction, the Constant score were 92 and 76 respectively. All of them got nearly normal range of motion of the shoulders and restored to pre-operative life and works. CONCLUSION: With this minimally invasive approach and limited exposure of the coracoid, a surgeon can place the suture anchors at the anatomical insertions of the coracoclavicular ligament and allow the dislocated joint reduced and maintained well. LEVEL OF EVIDENCE: Level IV, Case series; therapeutic study.

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OBJECTIVES: To establish the animal model of acute rotator cuff tear in rabbits, and study the effect of timing of surgical repair on healing of tendon-bone interface, formation and distribution of collagens in the supraspinatus tendon insertion and biomechanical properties of supraspinatus. METHODS: Supraspinatus tenotomy was performed in the right shoulder of 90 skeletally matured male New Zealand white rabbits to establish the animal model of acute rotator cuff tear. The rabbits were randomly divided into 3 groups : group of early repair, repaired at 1 week after tenotomy; group of late repair, repaired at 4 weeks after tenotomy; and group without repair, used as control. At 2 weeks, 4 weeks and 8 weeks after repair, healing of tendon-bone interface was observed by HE staining. Collagens were observed by Sirius Red F 3B (SR) in saturated carbazotic acid staining. The areas of type I and III collagens were measured by using imaging analysis software and the ratio of type I and III collagens were calculated. Failure loads of supraspinatus on both sides were measured. The percentage of failure loads of the surgical side was calculated and contralateral supraspinatus were uninjured. RESULTS: There was no obvious fatty infiltration and muscle atrophy in supraspinatus in all groups. At 8 weeks, the formation of a new enthesis of supraspinatus in groups of early and late repair were observed. In groups of early and late repair, the ratio of areas of type I and III collagens at 8 weeks (2.02 ± 0.77 and 2.06 ± 0.58) was larger than that at 2 weeks (1.10 ± 0.24 and 1.14 ± 0.50, t = 3.082, 3.655, P < 0.01). At 2, 4 and 8 weeks, the percentages of failure loads of the surgical side and uninjured contralateral supraspinatus in group of early repair(38% ± 11%, 66% ± 7%, 89% ± 4%) and group of late repair (41% ± 16%, 63% ± 7%, 89% ± 9%) were both higher than that in group without repair (14% ± 6%, 32% ± 4%, 56% ± 12%); the differences were all statistically significant (group of early repair: t = 3.311, 8.549, 5.719; group of late repair: t = 3.713, 8.063, 6.044; P < 0.01). The percentage of failure loads of the surgical side and uninjured contralateral supraspinatus at 8 weeks was higher than those at 4 weeks (t = 3.878 - 4.613, P < 0.01) and 2 weeks (t = 7.158 - 10.024, P < 0.01) in all groups. CONCLUSIONS: Surgical repair within 4 weeks of acute rotator cuff tear lead to formation of a new enthesis of supraspinatus, improvement of both ratio of type I collagen in the supraspinatus tendon insertion and biomechanical properties of supraspinatus.

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