A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Abstract

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.

Experimental Methods for Evaluating the Bacterial Uptake of Trojan Horse Antibacterials

“…It is common for the MICs of THAs to be determined against bacteria grown in both iron‐limited and iron‐sufficient conditions (Figure 5A). As iron uptake pathways are upregulated in response to iron limitation, an inverse correlation between iron concentration and antibacterial activity is often used to infer the utilisation of siderophore transport pathways by THA candidates [11,14–21] . A recent example can be found in work by Goldberg et al .…”

“…in the development of a γ‐lactam‐monocatechol conjugate, YU253434 (Figure 7). [18] After observing encouraging potencies against Pseudomonas aeruginosa PAO1, the MIC of YU253434 was re‐determined in iron‐limited MHII at various concentrations of supplemented iron(III) chloride. Encouragingly, the MIC increased with iron concentration in a similar fashion to the known THA cefiderocol, suggesting siderophore‐mediated uptake into the periplasm (Table 1), whereas no MIC change was observed for control compound ceftazidime (Figure 7).…”

“… Structures of YU253434 and ceftazidime [18] . For YU253434, antibacterial part in red and siderophore part in blue.…”

Advances in Understanding of the Copper Homeostasis in Pseudomonas aeruginosa

“…Another approach takes advantage of P. aeruginosa ’s own virulence factor. In that respect, a γ-lactam was conjugated to a siderophore moiety, taking advantage of the intrinsic siderophore uptake mechanism of P. aeruginosa [ 70 ]. These creative and effective strategies in combating emerging broad-spectrum resistance demonstrate that only continuing research and effort lead to novel antimicrobials eventually overcoming the multidrug resistance of P. aeruginosa .…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

“…The concept of using the siderophore importers present in Gram-negative bacteria to facilitate the intake of antibiotics into the periplasmic space [50] has been applied to the development of a new compound endowed with interesting activity against multidrug-resistant (MDR) bacteria. Goldberg et al [51] have reported the design, synthesis, structural characterization and antimicrobial activity of a novel pyrazolidinone antibiotic containing a dihydroxyphthalimide siderophore mimetic. The compound, dubbed YU253434, contains the 2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido moiety of ceftazidime linked to the pyrazolidinone nucleus, which in turn bears a dihydroxyphtalimide acting as a siderophore mimic (Figure 10).…”