Antibiotics in the clinical pipeline in October 2019

Butler, Mark S.; Paterson, David L.

doi:10.1038/s41429-020-0291-8

Cited by 222 publications

(207 citation statements)

References 294 publications

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“…Apramycin was proposed as a possible next-generation aminoglycoside, and it is currently the only new aminoglycoside in clinical development [ 9 , 10 ]. Apramycin is a monosubstituted 2-deoxystreptamine with an unusual bicyclic octose moiety on C4, providing significant structural differentiation from the 4,6-disubstituted deoxystreptamines gentamicin, tobramycin, amikacin, arbekacin, and plazomicin, which currently define the standard of care in treating infections with an aminoglycoside antibiotic.…”

Section: Introductionmentioning

confidence: 99%

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Plattner

Gysin

Haldimann

et al. 2020

IJMS

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Aminoglycoside antibiotics are powerful bactericidal therapeutics that are often used in the treatment of critical Gram-negative systemic infections. The emergence and global spread of antibiotic resistance, however, has compromised the clinical utility of aminoglycosides to an extent similar to that found for all other antibiotic-drug classes. Apramycin, a drug candidate currently in clinical development, was suggested as a next-generation aminoglycoside antibiotic with minimal cross-resistance to all other standard-of-care aminoglycosides. Here, we analyzed 591,140 pathogen genomes deposited in the NCBI National Database of Antibiotic Resistant Organisms (NDARO) for annotations of apramycin-resistance genes, and compared them to the genotypic prevalence of carbapenem resistance and 16S-rRNA methyltransferase (RMTase) genes. The 3-N-acetyltransferase gene aac(3)-IV was found to be the only apramycin-resistance gene of clinical relevance, at an average prevalence of 0.7%, which was four-fold lower than that of RMTase genes. In the important subpopulation of carbapenemase-positive isolates, aac(3)-IV was nine-fold less prevalent than RMTase genes. The phenotypic profiling of selected clinical isolates and recombinant strains expressing the aac(3)-IV gene confirmed resistance to not only apramycin, but also gentamicin, tobramycin, and paromomycin. Probing the structure–activity relationship of such substrate promiscuity by site-directed mutagenesis of the aminoglycoside-binding pocket in the acetyltransferase AAC(3)-IV revealed the molecular contacts to His124, Glu185, and Asp187 to be equally critical in binding to apramycin and gentamicin, whereas Asp67 was found to be a discriminating contact. Our findings suggest that aminoglycoside cross-resistance to apramycin in clinical isolates is limited to the substrate promiscuity of a single gene, rendering apramycin best-in-class for the coverage of carbapenem- and aminoglycoside-resistant bacterial infections.

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Section: Introductionmentioning

confidence: 99%

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Plattner

Gysin

Haldimann

et al. 2020

IJMS

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“…Gaining a mechanistic understanding of the plethora of activities of AMPs would be vital to fully comprehend structure-activity correlations. The mode of anti-bacterial activity of AMPs differs vastly from that of antibiotics which chiefly target intracellular macromolecules [24,25]. In many cases, both outer-LPS (in Gram negative) and inner bacterial membranes are permeabilized or disrupted upon binding to AMPs, leading to cell lysis.…”

Section: Introductionmentioning

confidence: 99%

“…A large number of studies have demonstrated that AMPs could be promising molecules for the treatment of drug resistant bacteria. However, to-date, very few AMPs are in the advanced stages of clinical trials [17,18,25] and most are being developed by smaller pharmaceutical companies. Reasons for these limited applications of AMPs are linked to the high cost of synthesis, low in vivo stability, host toxicity, and limited bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Design, Engineering and Discovery of Novel α-Helical and β-Boomerang Antimicrobial Peptides against Drug Resistant Bacteria

Bhattacharjya

Straus

2020

IJMS

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In an era where the pipeline of new antibiotic development is drying up, the continuous rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacteria are genuine threats to human health. Although antimicrobial peptides (AMPs) may serve as promising leads against drug resistant bacteria, only a few AMPs are in advanced clinical trials. The limitations of AMPs, namely their low in vivo activity, toxicity, and poor bioavailability, need to be addressed. Here, we review engineering of frog derived short α-helical AMPs (aurein, temporins) and lipopolysaccharide (LPS) binding designed β-boomerang AMPs for further development. The discovery of novel cell selective AMPs from the human proprotein convertase furin is also discussed.

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“…One of the latest breakthroughs in this area was the discovery of SQ109 [4], which is currently in Phase II/III clinical trials for the treatment of MDR pulmonary TB [5]. SQ109 belongs to the 1,2-ethylenediamine class of anti-TB drugs [6], consisting of adamantane head and geranyl tail, proposed to disrupt the synthesis of the complex Mtb cell wall [7].…”

Section: Introductionmentioning

confidence: 99%

Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450

Bukhdruker¹,

Varaksa²,

Grabovec³

et al. 2020

Preprint

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Spreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, the Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

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Antibiotics in the clinical pipeline in October 2019

Cited by 222 publications

References 294 publications

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV

Design, Engineering and Discovery of Novel α-Helical and β-Boomerang Antimicrobial Peptides against Drug Resistant Bacteria

Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450

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