Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Historically, natural products have played a critical role in bringing new therapies to the clinic to treat life-threatening bacterial infections. This Perspective provides an overview of antibiotic resistance and tolerance and highlights recent advances (chemistry, biology, drug discovery, and development) from various research programs involved in the discovery of new antibacterial agents inspired by a diverse series of natural product antibiotics.

Unlike individual, free-floating planktonic bacteria, biofilms are surface-attached communities of slow- or non-replicating bacteria encased within a protective extracellular polymeric matrix enabling persistent bacterial populations to tolerate high concentrations of antimicrobials. Our current antibacterial arsenal is composed of growth-inhibiting agents that target rapidly-dividing planktonic bacteria but not metabolically dormant biofilm cells. We report the first modular synthesis of a library of 20 halogenated phenazines (HP), utilizing the Wohl-Aue reaction, that targets both planktonic and biofilm cells. New HPs, including 6-substituted analogues, demonstrate potent antibacterial activities against MRSA, MRSE and VRE (MIC = 0.003–0.78 µM). HPs bind metal(II) cations and demonstrate interesting activity profiles when co-treated in a panel of metal(II) cations in MIC assays. HP 1 inhibited RNA and protein biosynthesis while not inhibiting DNA biosynthesis using 3H-radiolabeled precursors in macromolecular synthesis inhibition assays against MRSA. New HPs reported here demonstrate potent eradication activities (MBEC = 0.59–9.38 µM) against MRSA, MRSE and VRE biofilms while showing minimal red blood cell lysis or cytotoxicity against HeLa cells. PEG-carbonate HPs 24 and 25 were found to have potent antibacterial activities with significantly improved water solubility. HP small molecules could have a dramatic impact on persistent, biofilm-associated bacterial infection treatments.

Herein, we report a facile method for cholesterol detection by coupling the peroxidase-like activity of polypyrrole nanoparticles (PPy NPs) and cholesterol oxidase (ChOx). ChOx can catalyze the oxidation of cholesterol to produce H2O2. Subsequently, PPy NPs, as a nanozyme, induce the reaction between H2O2 and 3,3′,5,5′-tetramethylbenzidine (TMB). Under optimal conditions, the increase is proportional to cholesterol with concentrations from 10 to 800 μM in absorbance of TMB at 652 nm. The linear range for cholesterol is 10–100 μM, with a detection limit of 3.5 μM. This reported method is successfully employed for detection of cholesterol in human serum. The recovery percentage is ranged within 96–106.9%. Furthermore, we designed a facile and simple portable assay kit using the proposed system, realizing the on-site semiquantitative and visual detection of cholesterol in human serum. The cholesterol content detected from the portable assay kit were closely matching those obtained results from solution-based assays, thereby holding great potential in clinical diagnosis and health management.

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.

Tetracycline (TET) is a broad-spectrum antibiotic, which is frequently used in the prevention and treatment of animal diseases, feed additives, and so on. However, its residue and accumulation in animal-derived foods could cause several side effects to the human body. Herein, we fabricated TET aptamerpendant DNA tetrahedral nanostructure-functionalized magnetic beads (Apt-tet MBs) as a probe to detect TET. In the presence of target TET, DNA primer was released from Apt-tet MBs since the TET aptamer could specifically bind TET. Next, the separated DNA primer could effectively initiate rolling circle amplification (RCA) reaction and generate a long tandem single-stranded sequence. Finally, with SYBR Green I as the fluorescence dye, the fluorescence signal could be detected by detection probes through hybridizing the RCA product. Under optimal conditions, the fluorescent signal increased with the increasing target TET concentration within the 5 orders of magnitude dynamic range from 0.001 to 10 ng mL −1 . The detection limit was calculated to be 0.724 pg mL −1 and the method showed high selectivity toward TET among different antibiotics. More impressively, this method was employed for TET determination in fish and honey samples. The as-obtained results were consistent with those of ELISA kits, holding great potential in the field of food analysis.

At present, environmentally friendly biobased flexible films are of particular interest as next-generation fireproof packaging and sensor materials. To reduce the moisture uptake and fire risks induced by hygroscopic and flammable biobased films, we report a simple and green approach to develop a hydrophobic, flame-retardant composite film with synergetic benefit from soy protein isolate (SPI), sisal cellulose microcrystals (MSF-g-COOH), graphene nanosheets (GN), and citric acid (CA). Compared with SPI/MSF-g-COOH composite films, the as-prepared SPI/MSF-g-COOH/CA/GN composite films have significantly improved water resistance and can maintain excellent physical structure and good electrical conductivity in an ethanol flame. This work opens a pathway for the development of novel fire-retardant fire alarm biosensors.

Herein, we disclose the development of a catalyst- and protecting-group-free microwave-enhanced Friedländer synthesis which permits the single-step, convergent assembly of diverse 8-hydroxyquinolines with greatly improved reaction yields over traditional oil bath heating (increased from 34% to 72%). This rapid synthesis permitted the discovery of novel biofilm-eradicating halogenated quinolines (MBECs = 1.0-23.5 μM) active against MRSA, MRSE, and VRE. These small molecules exhibit activity through mechanisms independent of membrane lysis, further demonstrating their potential as a clinically useful treatment option against persistent biofilm-associated infections.

We report the synthesis and initial biological assessment of a halogenated phenazine–erythromycin conjugate prodrug 5 aimed to treat bacterial infections.