A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo

Wang, Xiaojian; Borges, Clarissa Araújo; Ning, Xinghai; Rafi, Mohammad; Zhang, Jingtuo; Park, Bora; Takemiya, Kiyoko; Sterzo, Claudio Lo; Taylor, W. Robert; Riley, Lee W.; Murthy, Niren

doi:10.1021/acs.bioconjchem.8b00177

Cited by 22 publications

(23 citation statements)

References 42 publications

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“…In parallel, data obtained from electrophysiology studies were consistent with these conclusions wherein Cpd-1 penetrates through reconstituted LamB channels better than Cpd-2. These general results wherein shorter saccharides provide improved accumulation are in agreement with recent results suggesting that a thiomaltose–perylene conjugate has better accumulation relative to a maltohexaose–perylene conjugate (26).…”

Section: Discussionsupporting

confidence: 91%

“…Several approaches have been explored to bypass these barriers including new adjuvants (permeabilizer, efflux pump inhibitors) to rejuvenate the antibacterial efficacy, Trojan horse strategies to hijack active transport pathways and provide efficient penetration, etc. However, crucial points with these strategies concern the internal biological activity and the precise localization of the molecule, and these aspects are generally not studied or reported in depth (25, 26).…”

Section: Discussionmentioning

confidence: 99%

“…This system comprises the maltoporin (LamB) that provides an efficient pathway for maltose penetration through the OM, the maltose binding protein (MalE) located in periplasm, maltodextrin transporters in the inner membrane (MalF, MalG, MalK) and various cytoplasmic degradative enzymes; these components are under the control of regulators belonging to maltose regulon (23). The internalization of a maltohexaose fluorophore (25), the uptake of a thiomaltose–trimethoprim conjugate (26), and the antibacterial activity of a radezolid analog (patent WO 2016/044846) have been recently reported. Interestingly, labeled-maltodextrins have also been used to study the localization/diagnosis of bacterial infections in mouse models of infection (27, 28).…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

et al. 2018

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

et al. 2018

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“…For example, agent‐based simulations revealed that the rate of prodrug activation (i.e., catalytic efficiency, k cat / K M ) had a strong effect on the MIC of each compound (Murphy et al , 2011 ). Furthermore, empirical studies have found there to be differences in MIC between parent and prodrug forms, as well as higher variance in prodrug MIC across bacterial strains, relative to the parent drug (Wang et al , 2018 ; Evans et al , 2019 ; Yang et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…We design the linker substrate to be cleaved by E. coli protease OmpT, such that increasing concentrations of bacteria activate higher concentrations of free AMP. The trimethoprim prodrug comprises thiomaltose conjugated to trimethoprim via a self‐immolative disulfide linker, which releases TMP‐OH upon cleavage by free thiols inside bacterial cells without affecting the toxicity of the drug (Wang et al , 2018 ). Free TMP‐OH then kills bacteria by inhibiting tetrahydrofolic acid synthesis, which is a necessary cofactor for thymidine, purine, and bacterial DNA synthesis (Masters et al , 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Dimensionless parameter predicts bacterial prodrug success

Holt

Tuttle

et al. 2022

Molecular Systems Biology

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Understanding mechanisms of antibiotic failure is foundational to combating the growing threat of multidrug‐resistant bacteria. Prodrugs—which are converted into a pharmacologically active compound after administration—represent a growing class of therapeutics for treating bacterial infections but are understudied in the context of antibiotic failure. We hypothesize that strategies that rely on pathogen‐specific pathways for prodrug conversion are susceptible to competing rates of prodrug activation and bacterial replication, which could lead to treatment escape and failure. Here, we construct a mathematical model of prodrug kinetics to predict rate‐dependent conditions under which bacteria escape prodrug treatment. From this model, we derive a dimensionless parameter we call the Bacterial Advantage Heuristic ( BAH ) that predicts the transition between prodrug escape and successful treatment across a range of time scales (1–10 4 h), bacterial carrying capacities (5 × 10 4 –10 5 CFU/µl), and Michaelis constants ( K M = 0.747–7.47 mM). To verify these predictions in vitro , we use two models of bacteria‐prodrug competition: (i) an antimicrobial peptide hairpin that is enzymatically activated by bacterial surface proteases and (ii) a thiomaltose‐conjugated trimethoprim that is internalized by bacterial maltodextrin transporters and hydrolyzed by free thiols. We observe that prodrug failure occurs at BAH values above the same critical threshold predicted by the model. Furthermore, we demonstrate two examples of how failing prodrugs can be rescued by decreasing the BAH below the critical threshold via (i) substrate design and (ii) nutrient control. We envision such dimensionless parameters serving as supportive pharmacokinetic quantities that guide the design and administration of prodrug therapeutics.

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Functional Materials to Overcome Bacterial Barriers and Models to Advance Their Development

Bali

Kamal

Mulla

et al. 2023

Adv Funct Materials

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With the emerging problem of antimicrobial resistance, the world is facing a slow but dangerous pandemic. While the discovery of novel antibiotics is reaching a nearly exhaustive end, new concepts for anti‐infective drugs are emerging. So‐called pathoblockers aim to de‐weaponize bacteria rather than just killing them. As the target of these molecules is typically located intracellularly, however, hitherto almost unnoticed biological barriers are emerging such as the biofilm matrix, the bacterial cell envelope, efflux pumps, and eventual bacterial metabolism. This leads to a new paradigm that is to maximize bacterial bioavailability. To overcome the bacterial barriers, especially when further optimization of the active molecules is not possible, functional materials are needed to engineer innovative delivery systems. Those may not only enable novel anti‐infective molecules to reach their targets, but will also improve the bacterial bioavailability of existing anti‐infectives. Additionally, there is a need for better infection models that allow studying drug effects on both the bacteria and the host in a relevant manner as needed for rational anti‐infective drug development.

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A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo

Cited by 22 publications

References 42 publications

Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

Dimensionless parameter predicts bacterial prodrug success

Functional Materials to Overcome Bacterial Barriers and Models to Advance Their Development

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