The Antibiotic Future

Silver, Lynn L.

doi:10.1007/7355_2017_24

Cited by 14 publications

(18 citation statements)

References 190 publications

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“…For siderophore–antibiotic conjugates, resistance can occur via OM transporter mutations or downregulation of siderophore uptake systems. 81,82 Ent–Cipro 2 can enter E. coli through FepA and IroN, and both transporters are important virulence factors that become upregulated during urinary tract infection. 73,74,83 It is possible that this feature makes resistance from OM transporter mutations less likely because both transporters would need to acquire loss-of-function mutations.…”

Section: Discussionmentioning

confidence: 99%

Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity

et al. 2018

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Enteric Gram-negative bacteria, including Escherichia coli, biosynthesize and deploy the triscatecholate siderophore enterobactin (Ent) in the vertebrate host to acquire iron, an essential nutrient. We report that Ent-Cipro, a synthetic siderophore-antibiotic conjugate based on the native Ent platform that harbors an alkyl linker at one of the catechols with a ciprofloxacin cargo attached, affords targeted antibacterial activity against E. coli strains that express the pathogen-associated iroA gene cluster. Attachment of the siderophore to ciprofloxacin, a DNA gyrase inhibitor and broad-spectrum antibiotic that is used to treat infections caused by E. coli, generates an inactive prodrug and guides the antibiotic into the cytoplasm of bacteria that express the Ent uptake machinery (FepABCDG). Intracellular hydrolysis of the siderophore restores the activity of the antibiotic. Remarkably, Fes, the cytoplasmic Ent hydrolase expressed by all E. coli, does not contribute to Ent-Cipro activation. Instead, this processing step requires IroD, a cytoplasmic hydrolase that is expressed only by E. coli that harbor the iroA gene cluster and are predominantly pathogenic. In the uropathogenic E. coli UTI89 and CFT073, Ent-Cipro provides antibacterial activity comparable to unmodified ciprofloxacin. This work highlights the potential of leveraging and targeting pathogen-associated microbial enzymes in narrow-spectrum antibacterial approaches. Moreover, because E. coli include harmless gut commensals as well as resident microbes that can contribute to disease, Ent-Cipro may provide a valuable chemical tool for strain-selective modulation of the microbiota.

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Section: Discussionmentioning

confidence: 99%

Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity

et al. 2018

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“…78 Combined analysis of these sobering high-throughput screening (HTS) data-lack of any new Gram-negative actives from the collective screening of >8 million compounds at GlaxoSmith-Kline, AstraZeneca, Merck, and others 77,78,80,84 -led to the conclusion that an improved understanding of compound penetration into Gram-negative bacteria would be necessary to make meaningful progress toward rational discovery/design of broadspectrum antibiotics, 78 and this call has been echoed by others. 74,[85][86][87][88]…”

Section: Gram-negative Bacteria As a Major Public Health Concernmentioning

confidence: 99%

The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

Richter

Hergenrother

2018

Annals of the New York Academy of Sciences

187

202

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Multidrug resistant Gram-negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram-negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These "eNTRy rules" state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.

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“…Due to the natural selective pressure exerted by exogenous agents, bacteria developed a plethora of resistance mechanisms to allow their survival in selective conditions and, consequently, significantly compromise the therapeutic efficacy of antibiotics [ 2 , 3 ]. Multidrug-resistant bacteria, now widespread in the clinical setting and potentially causing life-threatening infections, commonly exhibit a combination of resistance mechanisms, acting synergistically to both increase the level of resistance to individual drugs and broaden the resistance spectrum [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Although the latter are still potentially susceptible to hydrolysis, the hydrazide-like function is more chemically stable (Figure 1). In the first series, the carbon adjacent to the extra-cyclic nitrogen is sp 3 , whereas it is sp 2 in the second series as in the hydrazone-like function. The compounds were evaluated for their inhibitory activity on relevant MBLs, their ability to restore susceptibility to antibiotics in whole cell assays, as well as their mode of binding.…”

Section: Introductionmentioning

confidence: 99%

4-(N-Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

et al. 2020

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To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with Ki values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of β-lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL.

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The Antibiotic Future

Cited by 14 publications

References 190 publications

Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity

Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin–Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity

The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

4-(N-Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

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