Structure–Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds

Batchelder, Hunter R.; Zandi, Trevor A.; Kaushik, Amit; Naik, Akul; Story-Roller, Elizabeth; Maggioncalda, Emily C.; Lamichhane, Gyanu; Nuermberger, Eric L.; Townsend, Craig A.

doi:10.1021/acsinfecdis.2c00229

Cited by 4 publications

(5 citation statements)

References 45 publications

(90 reference statements)

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“…This mass difference corresponds to the addition of the sulopenem followed by post-acylation changes and fragmentation of the compound. This phenomenon stems from the distinctive cleavage of the C5-C6 bond, a mechanism previously reported in penems and carbapenems (20)(21)(22)(23). Sulopenem formed a +349 Da adduct with Ldt Mab3 , D,D-carboxypeptidase, and PBP B.…”

Section: Timed Electrospray Ionization Mass Spectrometry (Esi/ms) Cap...mentioning

confidence: 68%

Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus

Dousa,

Shin,

Kurz

et al. 2023

Preprint

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Mycobacterium abscessus(Mab) affects patients with immunosuppression, Cystic Fibrosis (CF), or underlying structural lung diseases. Additionally,Mabposes clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with a β-lactamase inhibitors [BLI; avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration MIC values for 54 clinicalMabisolates and ATCC19977 (MIC50and MIC90≤ 0.25 μg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ∼1.5 Log10CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in additional reduction of CFUs (∼3 Log10for sulopenem-CXM and AVI and ∼4 Log10for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (LDTs; LDTMab1–LDTMab4), Penicillin-Binding-Protein B (PBP-B), and D,D-Carboxypeptidase (DDC). Acyl complexes identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2-LdtMab4, DDC, and PBP B, and CXM with LdtMab2and PBP-B. Molecular docking suggested formation of a covalent adduct between sulopenem and LdtMab2after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring, and the establishment of a thioester bond linking the LdtMab2with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLI. These findings potentially broaden selection of oral therapeutic agents to combatMab.

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Section: Timed Electrospray Ionization Mass Spectrometry (Esi/ms) Cap...mentioning

confidence: 68%

Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus

Dousa,

Shin,

Kurz

et al. 2023

Preprint

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“…The C5α-methyl carbapenem showed decreased hydrolysis by BlaC but acylation rates of Ldt Mt2 comparable to meropenem. Likewise, penem modifications to the C2 side chain led to the identification of 23 as a potent antimicrobial against Ldt Mt2 of M. tuberculosis [212]. Compound 23 was shown to have an MIC of 0.5 µg/mL against the Mtb H 37 Rv strain.…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

“…Among these compounds, 24 showed potent activity against the multi-drug-resistant (MDR) S. aureus NRS70 strain (MIC values of 3.13 µg/mL). (21 [211], 22 [196], 23 [212], LYS228 [213], 24 [217], 25 [218], 26 [219], 27 [152], 28 [220], ETX0462 [221], 29 [222], 30 [223]).…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

“…Compound 25 consists of a dihydroxypyridone siderophore conjugated to a modified aminothiazoylglycyl cephalosporin. This modification allows the drug to be (21 [211], 22 [196], 23 [212], LYS228 [213], 24 [217], 25 [218], 26 [219], 27 [152], 28 [220], ETX0462 [221], 29 [222], 30 [223]).…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

“…The compound name in the original publication is provided in parenthesis. (21 [211], 22[196], 23[212], LYS228[213], 24[217], 25[218], 26[219], 27[152], 28[220], ETX0462[221], 29[222], 30[223]).…”

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confidence: 99%

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Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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Convenient and green synthesis of novel 1,2,5-trisubstituted benzimidazole compounds and their antibacterial activity evaluation

Liu

Luo

et al. 2023

J IRAN CHEM SOC

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Structure–Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds

Cited by 4 publications

References 45 publications

Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus

Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Convenient and green synthesis of novel 1,2,5-trisubstituted benzimidazole compounds and their antibacterial activity evaluation

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