New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria

Picconi, Pietro; Hind, Charlotte K.; Nahar, Kazi S.; Jamshidi, Shirin; Maggio, Lucia Di; Saeed, Naima; Evans, Bonnie; Solomons, Jessica; Wand, Matthew E.; Sutton, J. Mark; Rahman, Khondaker Miraz

doi:10.1021/acs.jmedchem.0c00328

Cited by 15 publications

(20 citation statements)

References 32 publications

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“…However, host-phage specificity requires that the pathogenic species has been identified before treatment can be started. Antibiotics do not have this issue as broadspectrum compounds are available [27][28][29]. This comes at a cost: broad-spectrum drugs such as the carbapenem class of antibiotics are known for their side effects, mostly due to the elimination of the natural bacterial flora [30][31][32].…”

Section: Broader Applications Of the Viruses Of Bacteriamentioning

confidence: 99%

Flagellotropic Bacteriophages: Opportunities and Challenges for Antimicrobial Applications

Esteves

Scharf

2022

IJMS

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Bacteriophages (phages) are the most abundant biological entities in the biosphere. As viruses that solely infect bacteria, phages have myriad healthcare and agricultural applications including phage therapy and antibacterial treatments in the foodservice industry. Phage therapy has been explored since the turn of the twentieth century but was no longer prioritized following the invention of antibiotics. As we approach a post-antibiotic society, phage therapy research has experienced a significant resurgence for the use of phages against antibiotic-resistant bacteria, a growing concern in modern medicine. Phages are extraordinarily diverse, as are their host receptor targets. Flagellotropic (flagellum-dependent) phages begin their infection cycle by attaching to the flagellum of their motile host, although the later stages of the infection process of most of these phages remain elusive. Flagella are helical appendages required for swimming and swarming motility and are also of great importance for virulence in many pathogenic bacteria of clinical relevance. Not only is bacterial motility itself frequently important for virulence, as it allows pathogenic bacteria to move toward their host and find nutrients more effectively, but flagella can also serve additional functions including mediating bacterial adhesion to surfaces. Flagella are also a potent antigen recognized by the human immune system. Phages utilizing the flagellum for infections are of particular interest due to the unique evolutionary tradeoff they force upon their hosts: by downregulating or abolishing motility to escape infection by a flagellotropic phage, a pathogenic bacterium would also likely attenuate its virulence. This factor may lead to flagellotropic phages becoming especially potent antibacterial agents. This review outlines past, present, and future research of flagellotropic phages, including their molecular mechanisms of infection and potential future applications.

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Section: Broader Applications Of the Viruses Of Bacteriamentioning

confidence: 99%

Flagellotropic Bacteriophages: Opportunities and Challenges for Antimicrobial Applications

Esteves

Scharf

2022

IJMS

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“…Interestingly, many of these PBD monomers also exhibited anti-bacterial activity against a range of Gram-positive bacteria, including methicillin-resistant Staphylococcus (Rahman et al, 2012). Another set of PBDs containing a terminal heteroaliphatic ring has similarly shown excellent activity against a panel of multidrug resistant Gram-negative bacteria (Picconi et al, 2020), without noticeable toxicity against eukaryotic cells. The therapeutic potential exhibited by PBD bi-aryl monomers (Andriollo et al, 2018; Brucoli et al, 2016; Picconi et al, 2020; Rahman et al, 2012; Rosado et al, 2011) is encouraging as they appear to possess significant anticancer and antibacterial activity and their eukaryotic toxicity can be tuned by altering the C8-side chain to make them selective against either eukaryotic or prokaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Requirement for specific bacterial genome maintenance pathways in repair of C8-linked pyrrolobenzodiazepine (PBD) bi-aryl monomer-mediated DNA damage

Joseph

Nahar

Daw

et al. 2022

Preprint

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Pyrrolobenzodiazepines (PBDs) are naturally occurring DNA binding compounds that possess anti-tumor and anti-bacterial activity. Chemical modifications of PBDs can result in improved DNA binding, sequence specificity and enhanced efficacy. More recently, synthetic PBD monomers have shown promise as payloads for antibody drug conjugates and antibacterial agents. The precise mechanism of action of these PBD monomers and their role in causing DNA damage remains to be elucidated. Here we characterized the damage-inducing potential of two C8-linked PBD bi-aryl monomers in Caulobacter crescentus and investigated the strategies employed by cells to repair the same. We show that these compounds cause DNA damage and efficiently kill bacteria, in a manner comparable to the extensively used DNA cross-linking agent mitomycin-C (MMC). However, in stark contrast to MMC which employs a mutagenic lesion tolerance pathway, we implicate essential functions for error-free mechanisms in repairing PBD monomer-mediated damage. We find that survival is severely compromised in cells lacking nucleotide excision repair and to a lesser extent, in cells with impaired recombination-based repair. Loss of nucleotide excision repair leads to significant increase in double-strand breaks, underscoring the critical role of this pathway in mediating repair of PBD-induced DNA lesions. Together, our study provides comprehensive insights into how mono-alkylating DNA-targeting therapeutic compounds like PBD monomers challenge cell growth, and identifies the specific mechanisms employed by the cell to counter the same.

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“…Therefore, it is important to explore diverse chemical scaffolds to develop new antibiotics that can be used to treat multiple-drug resistant infections. Recently, C8-linked pyrrolobenzodiazepines with a 3rd aliphatic-heterocycle have been identified as a new broad spectrum antibiotic class with activity against multidrug (MDR) bacteria including WHO priority pathogens 7 . This provided an important new chemical scaffold in our search for new broad-spectrum antibiotics and replenish the waning pipeline of antibiotic discovery.…”

Section: Introductionmentioning

confidence: 99%

N10-C11 Imine is Essential for Gram-negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines

Picconi¹,

Hind²,

Sutton³

et al. 2022

Preprint

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It is urgent to find new antibiotic classes to replenish the empty development pipeline of antibiotics. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and non-cytotoxic dilactam analogues to further understand the structure activity relationship and improve the safety potential of this class. The synthesized compounds were tested against panels of multidrug resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 – 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues while they were found to be inactive against MDR Gram-negative bacteria, with an MIC &gt;32 mg/L, compared to an MIC of 0.5 to 32 mg/L. A molecular modelling study suggests the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests the presence of N10-C11 imine moiety is crucial for broad spectrum activity of pyrrolobenzodiazepines.

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New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria

Cited by 15 publications

References 32 publications

Flagellotropic Bacteriophages: Opportunities and Challenges for Antimicrobial Applications

Flagellotropic Bacteriophages: Opportunities and Challenges for Antimicrobial Applications

Requirement for specific bacterial genome maintenance pathways in repair of C8-linked pyrrolobenzodiazepine (PBD) bi-aryl monomer-mediated DNA damage

N10-C11 Imine is Essential for Gram-negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines

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