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1. Novel Approaches for Treatment of Intraoral Microbial Infections

   https://doi.org/10.1177/00220345251317494  

   Hwang, G; Liu, Y; Korostoff, J (June 2025, Journal of Dental Research)

   Historically, broad-spectrum antibiotics have represented a major component of the therapeutic armamentarium used to treat common oral diseases associated with a bacterial etiology. The fact that these diseases are due to the accumulation of multispecies biofilms composed of ever-increasing numbers of resistant organisms has dramatically affected the efficacy of many of these drugs. Furthermore, it is now appreciated that repeated use of broad-spectrum antibiotics also affects the composition of the host commensal microbiota, which can have both local and systemic implications. In recognition of the limitations of classical antibiotics, alternative chemical, physical, and mechanical strategies are either in use or development. These include novel narrow-spectrum antimicrobials such as antitoxins, bacteriophages, and antibody-conjugated drugs that can target specific microbes while minimizing the emergence of resistant organisms and preserving eubiotic microbes. Other approaches, such as new broad-spectrum non-antibiotic strategies and probiotics, are aimed at disrupting or altering the composition of oral biofilms and their extracellular matrices to facilitate the elimination of overt pathogens by the host response and/or adjunctive antimicrobials. This critical review describes the use and limitations of broad- and narrow-spectrum strategies currently being used to treat common bacterially induced oral diseases as well as alternative methods in development. 

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2. Identification of the Biosynthetic Gene Cluster for the Organoarsenical Antibiotic Arsinothricin

   https://doi.org/10.1128/Spectrum.00502-21  

   Galván, Adriana E.; Paul, Ngozi P.; Chen, Jian; Yoshinaga-Sakurai, Kunie; Utturkar, Sagar M.; Rosen, Barry P.; Yoshinaga, Masafumi (September 2021, Microbiology Spectrum)

   Tang, Xiaoyu (Ed.)

   ABSTRACT The soil bacterium Burkholderia gladioli GSRB05 produces the natural compound arsinothricin [2-amino-4-(hydroxymethylarsinoyl) butanoate] (AST), which has been demonstrated to be a broad-spectrum antibiotic. To identify the genes responsible for AST biosynthesis, a draft genome sequence of B. gladioli GSRB05 was constructed. Three genes, arsQML , in an arsenic resistance operon were found to be a biosynthetic gene cluster responsible for synthesis of AST and its precursor, hydroxyarsinothricin [2-amino-4-(dihydroxyarsinoyl) butanoate] (AST-OH). The arsL gene product is a noncanonical radical S -adenosylmethionine (SAM) enzyme that is predicted to transfer the 3-amino-3-carboxypropyl (ACP) group from SAM to the arsenic atom in inorganic arsenite, forming AST-OH, which is methylated by the arsM gene product, a SAM methyltransferase, to produce AST. Finally, the arsQ gene product is an efflux permease that extrudes AST from the cells, a common final step in antibiotic-producing bacteria. Elucidation of the biosynthetic gene cluster for this novel arsenic-containing antibiotic adds an important new tool for continuation of the antibiotic era. IMPORTANCE Antimicrobial resistance is an emerging global public health crisis, calling for urgent development of novel potent antibiotics. We propose that arsinothricin and related arsenic-containing compounds may be the progenitors of a new class of antibiotics to extend our antibiotic era. Here, we report identification of the biosynthetic gene cluster for arsinothricin and demonstrate that only three genes, two of which are novel, are required for the biosynthesis and transport of arsinothricin, in contrast to the phosphonate counterpart, phosphinothricin, which requires over 20 genes. Our discoveries will provide insight for the development of more effective organoarsenical antibiotics and illustrate the previously unknown complexity of the arsenic biogeochemical cycle, as well as bring new perspective to environmental arsenic biochemistry. 

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3. Selection and horizontal gene transfer underlie microdiversity-level heterogeneity in resistance gene fate during wastewater treatment

   https://doi.org/10.1038/s41467-024-49742-8  

   Brown, Connor L; Maile-Moskowitz, Ayella; Lopatkin, Allison J; Xia, Kang; Logan, Latania K; Davis, Benjamin C; Zhang, Liqing; Vikesland, Peter J; Pruden, Amy (December 2024, Nature Communications)

   Abstract Activated sludge is the centerpiece of biological wastewater treatment, as it facilitates removal of sewage-associated pollutants, fecal bacteria, and pathogens from wastewater through semi-controlled microbial ecology. It has been hypothesized that horizontal gene transfer facilitates the spread of antibiotic resistance genes within the wastewater treatment plant, in part because of the presence of residual antibiotics in sewage. However, there has been surprisingly little evidence to suggest that sewage-associated antibiotics select for resistance at wastewater treatment plants via horizontal gene transfer or otherwise. We addressed the role of sewage-associated antibiotics in promoting antibiotic resistance using lab-scale sequencing batch reactors fed field-collected wastewater, metagenomic sequencing, and our recently developed bioinformatic tool Kairos. Here, we found confirmatory evidence that fluctuating levels of antibiotics in sewage are associated with horizontal gene transfer of antibiotic resistance genes, microbial ecology, and microdiversity-level differences in resistance gene fate in activated sludge. 

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4. Investigating Soil Microbiota for Antimicrobial Activity Against Safe Relatives of ESKAPE Pathogens

   Kim, E; O'besso, A; Graham, D; Graham, J (July 2025, Atlas journal of biology)

   According to the CDC, there are more than 2.8 million antibiotic resistant infections occurring in the United States each year, and more than 35,000 people die as a result (CDC 2019). Furthermore, the CDC classifies a group of bacteria known as ESKAPE pathogens as six emerging antibiotic-resistant pathogens that are difficult to eradicate with current antibiotics. Our study aims to identify and characterize soil-derived microorganisms with the potential to produce antimicrobial compounds effective against safe relatives of ESKAPE pathogens, with the goal of translating these findings to combat their pathogenic counterparts. We hypothesize that bacteria identified from the soil will inhibit the growth of the following nosocomial associated safe relatives Bacillus subtilis for E. faecium, Staphylococcus epidermidis for S. aureus, Escherichia coli for Klebsiella pneumoniae, Acinetobacter baylyi for A. baumannii, Pseudomonas putida for P. aeruginosa, and Enterobacter aerogenes for Enterobacter species. To test our hypothesis, soil samples were collected from Fayetteville State University (FSU) campus and serially diluted onto LB agar plates. Sixty-three distinct colonies were isolated and screened against non-pathogenic ESKAPE safe relatives. Of the 63 Fayetteville State University soil isolates (FSIs) screened, 12 (19%) exhibited antimicrobial activity against at least one of the six ESKAPE safe relatives, with all 12 inhibiting Acinetobacter baylyi and only FSI 15 demonstrating broad-spectrum inhibition. Characterization assays revealed that 11 of the 12 isolates were Gram-negative, catalase-positive, and motile; the single Gram-positive isolate (FSI 4) was catalase-negative and non-motile. All isolates displayed resistance to penicillin, while most remained susceptible to tetracycline and ciprofloxacin. These findings support our hypothesis that soil-derived bacteria can produce putative antimicrobial compounds effective against non-pathogenic ESKAPE safe relatives. This study underscores the potential of soil microbiota on the campus of Fayetteville State University as a source of novel antimicrobial agents capable of inhibiting antibiotic resistant ESKAPE pathogens and warrant further investigation into their therapeutic potential 

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5. Sub-inhibitory antibiotic treatment selects for enhanced metabolic efficiency

   https://doi.org/10.1128/spectrum.03241-23  

   Aduru, Sai Varun; Szenkiel, Karolina; Rahman, Anika; Ahmad, Mehrose; Fabozzi, Maya; Smith, Robert P.; Lopatkin, Allison J. (February 2024, Microbiology Spectrum)

   Zhang, Xue (Ed.)

   ABSTRACT Bacterial growth and metabolic rates are often closely related. However, under antibiotic selection, a paradox in this relationship arises: antibiotic efficacy decreases when bacteria are metabolically dormant, yet antibiotics select for resistant cells that grow fastest during treatment. That is, antibiotic selection counterintuitively favors bacteria with fast growth but slow metabolism. Despite this apparent contradiction, antibiotic resistant cells have historically been characterized primarily in the context of growth, whereas the extent of analogous changes in metabolism is comparatively unknown. Here, we observed that previously evolved antibiotic-resistant strains exhibited a unique relationship between growth and metabolism whereby nutrient utilization became more efficient, regardless of the growth rate. To better understand this unexpected phenomenon, we used a simplified model to simulate bacterial populations adapting to sub-inhibitory antibiotic selection through successive bottlenecking events. Simulations predicted that sub-inhibitory bactericidal antibiotic concentrations could select for enhanced metabolic efficiency, defined based on nutrient utilization: drug-adapted cells are able to achieve the same biomass while utilizing less substrate, even in the absence of treatment. Moreover, simulations predicted that restoring metabolic efficiency would re-sensitize resistant bacteria exhibiting metabolic-dependent resistance; we confirmed this result using adaptive laboratory evolutions ofEscherichia coliunder carbenicillin treatment. Overall, these results indicate that metabolic efficiency is under direct selective pressure during antibiotic treatment and that differences in evolutionary context may determine both the efficacy of different antibiotics and corresponding re-sensitization approaches. IMPORTANCEThe sustained emergence of antibiotic-resistant pathogens combined with the stalled drug discovery pipelines highlights the critical need to better understand the underlying evolution mechanisms of antibiotic resistance. To this end, bacterial growth and metabolic rates are often closely related, and resistant cells have historically been characterized exclusively in the context of growth. However, under antibiotic selection, antibiotics counterintuitively favor cells with fast growth, and slow metabolism. Through an integrated approach of mathematical modeling and experiments, this study thereby addresses the significant knowledge gap of whether antibiotic selection drives changes in metabolism that complement, and/or act independently, of antibiotic resistance phenotypes. 

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