Leveraging laboratory and clinical studies to design effective antibiotic combination therapy

Davis, Kathleen P.; Greenstein, Talia; Viau, Roberto; Aldridge, Bree B.

doi:10.1016/j.mib.2021.09.006

Cited by 7 publications

(4 citation statements)

References 74 publications

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“…Of note, the strong cooperative efflux between different drugs, such as chloramphenicol and cefamandole, and the simultaneous extrusion of the CH3-preferred drugs and the CH1- or CH2-preferred drugs have been observed ( 62 , 69 ). In the current clinical setting, combination therapies with more than one antibiotic have become a routine procedure, due to increased antibiotic resistance ( 70 ). In-depth understanding of the substrate polyspecificity mechanism for AcrAB−TolC, a major efflux pump in Gram-negative bacteria, might enable the development of a better strategy for a more effective combination therapy.…”

Section: Substrate Poly-specificity Of Acrab−tolcmentioning

confidence: 99%

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Jang

2023

BMB Rep

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Antibiotic resistance (AR) is a silent pandemic that kills millions worldwide. Although the development of new therapeutic agents against antibiotic resistance is in urgent demand, this has presented a great challenge, especially for Gram-negative bacteria that have inherent drug-resistance mediated by impermeable outer membranes and multidrug efflux pumps that actively extrude various drugs from the bacteria. For the last two decades, multidrug efflux pumps, including AcrAB−TolC, the most clinically important efflux pump in Gram-negative bacteria, have drawn great attention as strategic targets for re-sensitizing bacteria to the existing antibiotics. This article aims to provide a concise overview of the AcrAB−TolC operational mechanism, reviewing its architecture and substrate specificity, as well as the recent development of AcrAB−TolC inhibitors.

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Section: Substrate Poly-specificity Of Acrab−tolcmentioning

confidence: 99%

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Jang

2023

BMB Rep

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“…Understanding the potential for combination therapy is further complicated by the fact that these Gram-negative bacteria can cause infections at multiple sites ( 3 ). Thus, standard-rich media conditions (as defined by the European Committee on Antimicrobial Susceptibility Testing and the International Organization for Standardization) used for in vitro assays may not effectively predict how individual or combinations of antibiotics will interact in various distinct in vivo environments where bacterial metabolism can differ ( 18 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

Davis,

Morales,

Ende

et al. 2024

mBio

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The rise in infections caused by multidrug-resistant (MDR) bacteria has necessitated a variety of clinical approaches, including the use of antibiotic combinations. Here, we tested the hypothesis that drug-drug interactions vary in different media, and determined which in vitro models best predict drug interactions in the lungs. We systematically studied pair-wise antibiotic interactions in three different media, CAMHB, (a rich lab medium standard for antibiotic susceptibility testing), a urine mimetic medium (UMM), and a minimal medium of M9 salts supplemented with glucose and iron (M9Glu) with three Gram-negative ESKAPE pathogens, Acinetobacter baumannii (Ab), Klebsiella pneumoniae (Kp), and Pseudomonas aeruginosa (Pa). There were pronounced differences in responses to antibiotic combinations between the three bacterial species grown in the same medium. However, within species, PaO1 responded to drug combinations similarly when grown in all three different media, whereas Ab17978 and other Ab clinical isolates responded similarly when grown in CAMHB and M9Glu medium. By contrast, drug interactions in Kp43816, and other Kp clinical isolates poorly correlated across different media. To assess whether any of these media were predictive of antibiotic interactions against Kp in the lungs of mice, we tested three antibiotic combination pairs. In vitro measurements in M9Glu, but not rich medium or UMM, predicted in vivo outcomes. This work demonstrates that antibiotic interactions are highly variable across three Gram-negative pathogens and highlights the importance of growth medium by showing a superior correlation between in vitro interactions in a minimal growth medium and in vivo outcomes. IMPORTANCE Drug-resistant bacterial infections are a growing concern and have only continued to increase during the SARS-CoV-2 pandemic. Though not routinely used for Gram-negative bacteria, drug combinations are sometimes used for serious infections and may become more widely used as the prevalence of extremely drug-resistant organisms increases. To date, reliable methods are not available for identifying beneficial drug combinations for a particular infection. Our study shows variability across strains in how drug interactions are impacted by growth conditions. It also demonstrates that testing drug combinations in tissue-relevant growth conditions for some strains better models what happens during infection and may better inform combination therapy selection.

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“…Understanding the potential for combination therapy is further complicated by the fact that these Gram-negative bacteria can cause infections at multiple sites (3). Thus, standard rich media conditions (as defined by the European Committee on Antimicrobial Susceptibility Testing and the International Organization for Standardization) used for in vitro assays may not effectively predict how a combination will interact in various distinct in vivo environments where bacterial metabolism can differ (9). Here, we hypothesize that environmental effects on bacterial physiology influence drug interactions and that measurements taken using tissue mimetic media will be better able to predict in vivo outcomes.…”

Section: Introductionmentioning

confidence: 99%

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

Davis

Morales

McCabe

et al. 2022

Preprint

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The rise in infections caused by multidrug-resistant (MDR) bacteria has necessitated a variety of clinical approaches, including the use of antibiotic combinations. Antibiotic susceptibility is affected in part by the growth state of bacteria within various tissues. Here we tested the hypothesis that drug-drug interactions vary in different media, and hence, using a medium that reflects tissue environments will better predict in vivo outcomes. We systematically studied pair-wise antibiotic interactions in three different media (CAMHB, a urine mimetic, and a lung mimetic) using three Gram-negative ESKAPE pathogens, Acinetobacter baumannii (Ab), Klebsiella pneumoniae (Kp), and Pseudomonas aeruginosa (Pa). There were pronounced differences in responses to antibiotic combinations between the three bacterial species grown in the same medium. However, within species, Pa responded to drug combinations similarly when grown in all three different media, whereas Ab responded similarly when grown in CAMHB and a lung mimetic medium. By contrast, drug interactions in Kp were poorly correlated across three different media. To assess whether distinct media were predictive of antibiotic interactions in Kp in the lungs of mice, we developed a treatment strategy and tested three antibiotic combination pairs. Measurements obtained in vitro from lung mimetic medium, but not rich medium, predicted in vivo outcomes. This work demonstrates that antibiotic interactions are highly variable when comparing across three gram-negative pathogens and highlights the importance of growth medium by showing a superior correlation between in vitro interactions in a growth medium that resembles the tissue environment and in vivo outcomes.

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Leveraging laboratory and clinical studies to design effective antibiotic combination therapy

Cited by 7 publications

References 74 publications

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses

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