Novel Targets and Mechanisms in Antimicrobial Drug Discovery

Tondi, Donatella

doi:10.3390/antibiotics10020141

Cited by 6 publications

(5 citation statements)

References 11 publications

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“…As there are still compounds with uncharacterized MOA [ 211 ] or antibiotics where the direct physical interactions with the target (e.g., ribosome) are largely unexplored [ 145 ] (e.g., AZ7), the optimization and development of new assays, including novel targets that can be used as tools in antibiotic development and approval, are essential [ 212 , 213 , 214 ]. Furthermore, it is expected that new compounds with unknown MOA will be isolated from natural sources in the future.…”

Section: Discussionmentioning

confidence: 99%

Overview on Strategies and Assays for Antibiotic Discovery

2022

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The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement.

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Section: Discussionmentioning

confidence: 99%

Overview on Strategies and Assays for Antibiotic Discovery

2022

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“…To date, microbial resistance remains a serious threat to humankind, representing a major global concern (Iscla et al 2015;Dinghra et al 2020;Tondi 2021;Pariente et al 2022). Although it was later questioned by de Krakter et al (2016), O'Neil (2014 predicted that by 2050, microbial resistance would be a leading cause of death, claiming 50 million lives each year.…”

Section: Drug Likeness and Adme Evaluationmentioning

confidence: 99%

“…Infectious diseases remain a profound and global health concern for humanity, posing a substantial threat to public health (Iscla et al 2015;Dinghra et al 2020;Tondi 2021;Pariente et al 2022). Despite their debatability (de Kraker et al 2016), they are expected to cause an estimated 10 million deaths annually by 2050 (O'Neil 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Despite their debatability (de Kraker et al 2016), they are expected to cause an estimated 10 million deaths annually by 2050 (O'Neil 2014). However, while bacterial infections are on the rise, the advancement of new antibiotic discoveries in both preclinical and clinical stages has stagnated (WHO 2021;Tondi 2021). According to The World Health Organization (WHO), only twelve antibiotics have received FDA approval since 2017, notably ten belonging to known classes featuring recognized mechanisms of antimicrobial resistance.…”

Section: Introductionmentioning

confidence: 99%

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Antimicrobial and FAD synthetases modulating activities of leporins A-C isolated from the sponge-associated fungus Trichoderma sp.

LOSUNG,

GINTING,

ABDJUL

et al. 2023

Biodiversitas

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Abstract. Losung F, Ginting EL, Abdjul B, Kapojos MM, Maarisit W, Mentang F, Sumilat DA, Balansa W, Mangindaan REP. 2023. Antimicrobial and FAD synthetases modulating activities of leporins A-C isolated from the sponge-associated fungus Trichoderma sp. Biodiversitas 24: 6502-6515. The emergence of microbial resistance poses a formidable threat to human health, requiring the discovery of new antibiotics. In this study, we investigated the antimicrobial potential and molecular structures of the metabolites produced by a sponge's symbiont fungal species, Trichoderma sp., in vitro against S. aureus IAM 12544T and Candida albicans IFM 4954 and in-silico against the emerging antibacterial target, prokaryotic bifunctional synthetases (FADS). The molecular structures were determined using spectroscopic techniques (1D, 2D NMR, HRESIMS), while the assessment of biological activities, physicochemical properties, and molecular modifications was performed through a slightly modified disk agar diffusion method, molecular docking, SwissAdme and pkCMS tools, and bioisosterism, respectively. The analysis of spectroscopic data supported the identification of leporins A-C (1-3) as the metabolites, which exhibited strong binding affinities against the 2X0K protein target (-8.9 to -9.4 kcal/mol). Despite their being slightly weaker than known FADS modulators such as compounds 4 (-10.5 kcal/mol) and 5 (-10.5 kcal/mol), leporins A-C demonstrated a stronger binding affinity than compound 6 (-9.6 to -10.5 kcal/mol). Notably, substituting a methyl group with a fluorine atom in 1-3 resulted in lepofluorins A-C (1a-3a), which exhibited enhanced binding affinities and improved physicochemical properties compared to the existing FADS modulators. These findings suggest that leporins A-C (1-3), particularly lepofluorins A-C (1a-3a), have potential as putative novel modulators of FADS. This study provides valuable insights into the design and development of new antibiotics to combat microbial resistance.

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“…To cope with this disease burden, new therapeutic biomarkers and drug targets are required. New targets may have useful mechanisms [ 26 ] that can be harnessed to render the bacteria inactive when bound by drug. Next-generation sequencing (NGS) technology has made it simpler to acquire genetic data of microbial species [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Alturki

Mashraqi

Jalal

et al. 2022

Cancers

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Colorectal cancer (CRC) ranks third among all cancers in terms of prevalence. There is growing evidence that gut microbiota has a role in the development of colorectal cancer. Fusobacterium nucleatum is overrepresented in the gastrointestinal tract and tumor microenvironment of patients with CRC. This suggests the role of F. nucleatum as a potential risk factor in the development of CRC. Hence, we aimed to explore whole genomes of F. nucleatum strains related to CRC to predict potential therapeutic markers through a pan-genome integrated subtractive genomics approach. In the current study, we identified 538 proteins as essential for F. nucleatum survival, 209 non-homologous to a human host, and 12 as drug targets. Eventually, riboflavin synthase (RiS) was selected as a therapeutic target for further processing. Three different inhibitor libraries of lead-like natural products, i.e., cyanobactins (n = 237), streptomycins (n = 607), and marine bacterial secondary metabolites (n = 1226) were screened against it. After the structure-based study, three compounds, i.e., CMNPD3609 (−7.63) > Malyngamide V (−7.03) > ZINC06804365 (−7.01) were prioritized as potential inhibitors of F. nucleatum. Additionally, the stability and flexibility of these compounds bound to RiS were determined via a molecular dynamics simulation of 50 ns. Results revealed the stability of these compounds within the binding pocket, after 5 ns. ADMET profiling showed compounds as drug-like, non-permeable to the blood brain barrier, non-toxic, and HIA permeable. Pan-genomics mediated drug target identification and the virtual screening of inhibitors is the preliminary step towards inhibition of this pathogenic oncobacterium and we suggest mouse model experiments to validate our findings.

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Novel Targets and Mechanisms in Antimicrobial Drug Discovery

Abstract: The spread of infections resistant to available anti-infective drugs is a serious menace to human health [...]

Cited by 6 publications

References 11 publications

Overview on Strategies and Assays for Antibiotic Discovery

Overview on Strategies and Assays for Antibiotic Discovery

Antimicrobial and FAD synthetases modulating activities of leporins A-C isolated from the sponge-associated fungus Trichoderma sp.

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

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