In Vitro Activity of a Novel Siderophore-Cephalosporin LCB10-0200 (GT-1), and LCB10-0200/Avibactam, against Carbapenem-Resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa Strains at a Tertiary Hospital in Korea

Nguyen, Le Phuong Anh; Park, Chul Soon; Pinto, Naina Adren; Lee, Hyun‐Sook; Seo, Hyun Soo; Vu, Thao Nguyen; Mai, Hung; Pham, An Huynh Thuy; Jang, Eris; Cho, Young Lag; Goglin, Karrie; Nguyen, Kevin; White, Richard C.; D’Souza, Roshan; Fouts, Derrick E.; Yong, Dongeun

doi:10.3390/ph14040370

Cited by 7 publications

(4 citation statements)

References 57 publications

(38 reference statements)

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“…Moreover, the results demonstrate that in this Amp-resistant strain, siderophore conjugation can still enhance activity so long as the warhead is preserved. This result opens new doors regarding SAC activity against Kp, which is relatively understudied in the field, and illuminates the possibility of SAC utilization within combination therapies. , It also motivates the study of conjugates employing more advanced, β-lactamase resistant warheads, such as meropenem, to target β-lactamase-producing strains.…”

Section: Resultsmentioning

confidence: 93%

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens

Motz,

Guo,

Sargun

et al. 2024

J. Am. Chem. Soc.

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Developing new antibiotics and delivery strategies is of critical importance for treating infections caused by Gramnegative bacterial pathogens. Hijacking bacterial iron uptake machinery, such as that of the siderophore enterobactin (Ent), represents one promising approach toward these goals. Here, we report a novel Ent-inspired siderophore−antibiotic conjugate (SAC) employing an alternative siderophore moiety as the delivery vector and demonstrate the potency of our SACs harboring the βlactam antibiotic ampicillin (Amp) against multiple pathogenic Gram-negative bacterial strains. We establish the ability of N,N',N''-(nitrilotris(ethane-2,1-diyl))tris(2,3-dihydroxybenzamide) (TRENCAM, hereafter TC), a synthetic mimic of Ent, to facilitate drug delivery across the outer membrane (OM) of Gram-negative pathogens. Conjugation of Amp to a new monofunctionalized TC scaffold affords TC-Amp, which displays markedly enhanced antibacterial activity against the gastrointestinal pathogen Salmonella enterica serovar Typhimurium (STm) compared with unmodified Amp. Bacterial uptake, antibiotic susceptibility, and microscopy studies with STm show that the TC moiety facilitates TC-Amp uptake by the OM receptors FepA and IroN and that the Amp warhead inhibits penicillin-binding proteins. Moreover, TC-Amp achieves targeted activity, selectively killing STm in the presence of a commensal lactobacillus. Remarkably, we uncover that TC-Amp and its Ent-based predecessor Ent-Amp achieve enhanced antibacterial activity against diverse Gram-negative ESKAPE pathogens that express Ent uptake machinery, including strains that possess intrinsic β-lactam resistance. TC-Amp and Ent-Amp exhibit potency comparable to that of the FDA-approved SAC cefiderocol against Gram-negative pathogens. These results demonstrate the effective application of native and appropriately designed nonnative siderophores as vectors for drug delivery across the OM of multiple Gram-negative bacterial pathogens.

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Section: Resultsmentioning

confidence: 93%

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens

Motz,

Guo,

Sargun

et al. 2024

J. Am. Chem. Soc.

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“…The Battle against Antibiotic Resistance: Novel Therapeutic Options for Acinetobacter… DOI: http://dx.doi.org/10.5772/intechopen.1003617 siderophore cephalosporins utilize a "trojan-horse approach" to evade resistance mechanisms in Gram-negative bacteria [82]. However, available clinical data for cefiderocol are conflicting, leaving infectious disease specialists uncertain about its optimal use in clinical practice.…”

Section: New Antibioticsmentioning

confidence: 99%

The Battle Against Antibiotic Resistance: Novel Therapeutic Options for Acinetobacter baumannii

Emami,

Pirbonyeh,

Javanmardi

2023

Acinetobacter Baumannii - The Rise of a Resistant Pathogen

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Undoubtedly, Acinetobacter baumannii stands out as one of the most effective bacteria responsible for nosocomial infections within the healthcare system. Due to its multidrug-resistant nature and the frequency of outbreaks that it causes the treatment of infections caused by this bacterium is challenging, antimicrobial combination therapy has been utilized to treat multidrug resistance Gram-negatives when monotherapy is ineffective. In contrast to antibiotics or short peptides, which possess only the capacity to bind and regulate a specific target, antibodies exhibit supplementary properties attributed to their Fc region, including opsonophagocytic activity, the agglutination process, and activation of the complement system. The criticality of antibodies is exemplified in triggering immunity against A. baumannii, stimulating protective mechanisms, preventing bacterial attachment to epithelial cells, opsonization, and complement-dependent bacterial destruction. Given antibodies’ significant role in humoral immunity, monoclonal antibodies (mAbs) may be generated to specifically bind to certain targets, thereby providing supplemental defense as a form of immunotherapy or passive immunization. Many encouraging tactics, ranging from phage therapy to immunotherapy, are being scrutinized for their efficacy in treating infectious diseases, thus shaping the future treatment landscape.

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“…В качестве еще одного примера конъюгата сиде рофорантибиотик, содержащего железохелатирую щий дигидроксопиридоновый фрагмент, стоит отметить GT1 64 [148,149] (Рисунок 28).…”

Section: конъюгаты сидерофор-антибиотик содержащие дигидропиридоновый...unclassified

Siderophore‑antibiotic conjugates: structural diversity and antibacterial activity

Chernyshov

Kuzovlev

Cherepanova

et al. 2022

CMAC

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Due to uncontrolled growth of antimicrobial resistance, in the near future humanity may return to the «pre-antibiotic era» with no reliable antimicrobial therapy even for previously easily treatable infectious diseases. One of possible solutions is improved delivery of antibiotics to antibiotic-resistant bacterial strains by conjugating them with siderophores (small molecules secreted by microorganisms to absorb essential Fe(III)). The siderophore-modified antibiotic (sideromycin), like a Trojan horse, permeates the bacterial cell as a complex with Fe(III), allowing the antibiotic to reach its biological target. In this review, we describe the structural diversity of siderophore-antibiotic conjugates with the focus on the structure of sideromycin as well as on the relationship between the structure of sideromycin and its antibacterial activity. We analyze main representatives of various classes of siderophores; the structural diversity of sideromycins and their antibacterial activity discussed in detail.

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In Vitro Activity of a Novel Siderophore-Cephalosporin LCB10-0200 (GT-1), and LCB10-0200/Avibactam, against Carbapenem-Resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa Strains at a Tertiary Hospital in Korea

Cited by 7 publications

References 57 publications

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens

The Battle Against Antibiotic Resistance: Novel Therapeutic Options for Acinetobacter baumannii

Siderophore‑antibiotic conjugates: structural diversity and antibacterial activity

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