Repurposing Antibiotics to Treat Resistant Gram‐Negative Pathogens

Schweizer, Frank

doi:10.1002/9781119282549.ch18

Cited by 3 publications

(2 citation statements)

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“…The best-studied example of an OM-disrupting synergist is polymyxin B nonapeptide (PMBN), which is obtained by enzymatic degradation of the clinically used lipopeptide polymyxin B (PMB). , The potentiating effects of PMBN were first reported in the 1980s, and in the decades since, a growing number of OM-disrupting synergists have been discovered. ,, To date, a number of reviews have been published on the general topic of antibiotic synergy, − including compounds that potentiate Gram-positive antibiotics through interactions with the OM and OM-disrupting synergists. ,− However, a comprehensive overview of OM-disrupting synergists that also provides the reader with a direct comparison of both the potency and selectively of these compounds has, to date, been lacking. In this regard, the most widely accepted benchmark for synergistic activity is the so-called fractional inhibitory concentration index (FICI, Box ).…”

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Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae , and/or Acinetobacter baumannii . In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

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Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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“…This is made possible by lowering the minimum inhibitory concentration of the antibiotic required to kill the bacteria and allowing for the preservation of currently available treatment options ( Melander and Melander, 2017 ; Laws et al., 2019 ). Repurposing the antibacterial compounds rendered obsolete ( Schweizer, 2019 ), ( Boyd et al., 2021 ) opens up the possibility of developing numerous analogues as antibiotic adjuvants. Moreover, the combination of adjuvants with antibiotics has the potential to reduce the rates of bacterial mutations, which has the potential to slow the development of resistance because of the well-conserved putative bacterial target ( Allen & Brown, 2019 ).…”

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Antibiotic adjuvants: synergistic tool to combat multi-drug resistant pathogens

Kumar,

Yasmeen,

Pandey

et al. 2023

Front. Cell. Infect. Microbiol.

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The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies are being explored to enhance the effectiveness of antibiotics. Antibiotic adjuvants have emerged as a promising approach to combat MDR pathogens by acting synergistically with antibiotics. This review focuses on the role of antibiotic adjuvants as a synergistic tool in the fight against MDR pathogens. Adjuvants refer to compounds or agents that enhance the activity of antibiotics, either by potentiating their effects or by targeting the mechanisms of antibiotic resistance. The utilization of antibiotic adjuvants offers several advantages. Firstly, they can restore the effectiveness of existing antibiotics against resistant strains. Adjuvants can inhibit the mechanisms that confer resistance, making the pathogens susceptible to the action of antibiotics. Secondly, adjuvants can enhance the activity of antibiotics by improving their penetration into bacterial cells, increasing their stability, or inhibiting efflux pumps that expel antibiotics from bacterial cells. Various types of antibiotic adjuvants have been investigated, including efflux pump inhibitors, resistance-modifying agents, and compounds that disrupt bacterial biofilms. These adjuvants can act synergistically with antibiotics, resulting in increased antibacterial activity and overcoming resistance mechanisms. In conclusion, antibiotic adjuvants have the potential to revolutionize the treatment of MDR pathogens. By enhancing the efficacy of antibiotics, adjuvants offer a promising strategy to combat the growing threat of antibiotic resistance. Further research and development in this field are crucial to harness the full potential of antibiotic adjuvants and bring them closer to clinical application.

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