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1. Ladder-shaped microfluidic system for rapid antibiotic susceptibility testing

   https://doi.org/10.1038/s44172-023-00064-5  

   Nguyen, Ann V. ; Yaghoobi, Mohammad ; Azizi, Morteza ; Davaritouchaee, Maryam ; Simpson, Kenneth W. ; Abbaspourrad, Alireza ( April 2023 , Communications Engineering)

   Rapid identification of antibiotic-resistant bacteria will play a key role in solving the global antibiotic crisis by providing a route to targeted antibiotic administration. However, current bacterial infection diagnoses take up to 3 days which can lead to antibiotic treatment that is less effective. Here we report a microfluidic system with a ladder shaped design allowing us to generate a twofold serial dilution of antibiotics comparable to current national and international standards. Our consolidated design, with minimal handling steps cuts down the testing time for antibiotic susceptibility from 16–20 h to 4–5 h. Our feasibility testing results are consistent with the commercial antibiotic susceptibility testing (AST) results, showing a 91.75% rate of agreement for Gram-negative and Gram-positive bacterial isolated from canine urinary tract infections (UTI) and may be used without prior isolation or enrichment. This platform provides an adaptable and efficient diagnostic tool for antibiotic susceptibility testing.

    

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2. Modification of narrow‐spectrum peptidomimetic polyurethanes with fatty acid chains confers broad‐spectrum antibacterial activity

   https://doi.org/10.1002/pi.5773  

   Peng, Chao ; Zhang, Tian ; Ortiz‐Ortiz, Deliris N. ; Vishwakarma, Apoorva ; Barton, Hazel A. ; Joy, Abraham ( February 2019 , Polymer International)

   Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such asEscherichia coli; however, these polymers are not effective against Gram‐positive bacteria, such asStaphylococcus aureus. With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such asS. aureus, however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical Industry

    

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3. Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria

   https://doi.org/10.1111/cbdd.13930  

   Zeiders, Samantha M. ; Chmielewski, Jean ( August 2021 , Chemical Biology & Drug Design)

   The failure to treat everyday bacterial infections is a current threat as pathogens are finding new ways to thwart antibiotics through mechanisms of resistance and intracellular refuge, thus rendering current antibiotic strategies ineffective. Cell‐penetrating peptides (CPPs) are providing a means to improve antibiotics that are already approved for use. Through coadministration and conjugation of antibiotics with CPPs, improved accumulation and selectivity with alternative and/or additional modes of action against infections have been observed. Herein, we review the recent progress of this antibiotic–cell‐penetrating peptide strategy in combatting sensitive and drug‐resistant pathogens. We take a closer look into the specific antibiotics that have been enhanced, and in some cases repurposed as broad‐spectrum drugs. Through the addition and conjugation of cell‐penetrating peptides to antibiotics, increased permeation across mammalian and/or bacterial membranes and a broader range in bacterial selectivity have been achieved.

    

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4. Randomized Trial Evaluating Clinical Impact of RAPid IDentification and Susceptibility Testing for Gram-negative Bacteremia: RAPIDS-GN

   Banerjee R. ; Komarow L. ; Virk A. ; Rajapakse N. ; Schuetz A. ; Dylla B. ; Earley M. ; Lok J.J. ; Kohner P. ; Ihde S. ; et al ( July 2021 , Clinical infectious diseases)

   Background. Rapid blood culture diagnostics are of unclear benefit for patients with gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, randomized, controlled trial comparing outcomes of patients with GNB BSIs who had blood culture testing with standard-of-care (SOC) culture and antimicrobial susceptibility testing (AST) vs rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno System (RAPID). Methods. Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship (AS) review or RAPID with AS. The primary outcome was time to first antibiotic modification within 72 hours of randomization. Results. Of 500 randomized patients, 448 were included (226 SOC, 222 RAPID). Mean (standard deviation) time to results was faster for RAPID than SOC for organism ID (2.7 [1.2] vs 11.7 [10.5] hours; P < .001) and AST (13.5 [56] vs 44.9 [12.1] hours; P < .001). Median (interquartile range [IQR]) time to first antibiotic modification was faster in the RAPID arm vs the SOC arm for overall antibiotics (8.6 [2.6–27.6] vs 14.9 [3.3–41.1] hours; P = .02) and gram-negative antibiotics (17.3 [4.9–72] vs 42.1 [10.1–72] hours; P < .001). Median (IQR) time to antibiotic escalation was faster in the RAPID arm vs the SOC arm for antimicrobial-resistant BSIs (18.4 [5.8–72] vs 61.7 [30.4–72] hours; P = .01). There were no differences between the arms in patient outcomes. Conclusions. Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for gram-negative BSIs. 

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5. Role of internal loop dynamics in antibiotic permeability of outer membrane porins

   https://doi.org/10.1073/pnas.2117009119  

   Vasan, Archit Kumar ; Haloi, Nandan ; Ulrich, Rebecca Joy ; Metcalf, Mary Elizabeth ; Wen, Po-Chao ; Metcalf, William W. ; Hergenrother, Paul J. ; Shukla, Diwakar ; Tajkhorshid, Emad ( February 2022 , Proceedings of the National Academy of Sciences)

   Andrej Sali, Bioengineering & (Ed.)

   Antibiotic resistance in Gram-negative pathogens has been identified as an urgent threat to human health by the World Health Organization. The major challenge with treating infections by these pathogens is developing antibiotics that can traverse the dense bacterial outer membrane (OM) formed by a mesh of lipopolysaccharides. Effective antibiotics permeate through OM porins, which have evolved for nutrient diffusion; however, the conformational states of these porins regulating permeation are still unclear. Here, we used molecular dynamics simulations, free energy calculations, Markov-state modeling, and whole-cell accumulation assays to provide mechanistic insight on how a porin shifts between open and closed states. We provide a mechanism of how Gram-negative bacteria confer resistance to antibiotics.

    

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