Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial

Jager, Veronique de; Gupte, Nikhil; Nunes, Silvia; Barnes, Grace L.; Wijk, Rob C. van; Mostert, Joni; Dorman, Susan E.; Abulfathi, Ahmed A.; Upton, Caryn M.; Faraj, Alan; Nuermberger, Eric L.; Lamichhane, Gyanu; Svensson, Elin M; Keutzer, Lina; Diacon, Andreas H.; Dooley, Kelly E.

doi:10.1164/rccm.202108-1976oc

Cited by 23 publications

(29 citation statements)

References 24 publications

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“…Analyzing the expression levels of PG synthesis genes did not reveal why UDP-GlcNAc levels are altered by RRDR mutations, but the downstream effects of this altered metabolite can account for differences in sensitivity to β-lactams. β-lactams are some of the most powerful antibiotics and are being considered in TB therapy with RIF (33). Thus, this work on evolution of resistance to the combination of RIF and CEF, the collateral sensitivity to CEF on acquisition of RIF resistance, and the differential response of rpoB mutants to CEF will benefit future studies designing effective drug treatments.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to mutants evolved under combination selection (S487L), the H482Y mutation made cells highly susceptible to CEF (32X more sensitive than WT), whereas the Q469R mutation led to a modest increase in CEF resistance (2X more resistant than WT). Combination treatment using RIF and β-lactams has been proposed as a potential drug therapy for M. tuberculosis (33). We therefore tested whether two common RIF resistant mutations in M. tuberculosis (S531L and H526Y) also alter CEF susceptibility.…”

Section: Rpob Mutants Exhibit Altered Susceptibility To Other Cell Wa...mentioning

confidence: 99%

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Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

Patel

Soni

Rhee

et al. 2022

Preprint

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Bacteria can adapt to stressful conditions through mutations affecting the RNA polymerase core subunits that lead to beneficial changes in transcription. In response to selection with rifampicin (RIF), mutations arise in the RIF resistance determining region (RRDR) ofrpoBthat reduce antibiotic binding. These changes can also alter transcription and thereby have pleiotropic effects on bacterial fitness. Here, we studied the evolution of resistance in Bacillus subtilis to the synergistic combination of RIF and the β-lactam cefuroxime (CEF). Two independent evolution experiments led to the recovery of a single rpoB allele (S487L) that was able to confer resistance to RIF and CEF through a single mutation. Two other common RRDR mutations made the cells 32x more sensitive to CEF (H482Y) or led to only modest CEF resistance (Q469R). The diverse effects of these three mutations on CEF resistance are correlated with differences in the expression of peptidoglycan (PG) synthesis genes and in the levels of two metabolites crucial in regulating PG synthesis, glucosamine-6-phosphate (GlcN-6-P) and UDP-N-acetylglucosamine (UDP-GlcNAc). We conclude that RRDR mutations can have widely varying effects on pathways important for cell wall biosynthesis, and this may restrict the spectrum of mutations that arise during combination therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Rpob Mutants Exhibit Altered Susceptibility To Other Cell Wa...mentioning

confidence: 99%

Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

Patel

Soni

Rhee

et al. 2022

Preprint

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“…Meropenem is only available as an intravenous medication. A recently published trial demonstrated that it has to be given three times daily to be effective, which is impractical for outpatients requiring the medication for 6 months, and it was frequently associated with gastrointestinal side effects [ 96 ].…”

Section: Mycobacterial Cell Wallmentioning

confidence: 99%

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Edwards

Field

2022

Drugs

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This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.

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“…For example, meropenem is highly effective in vitro when combined with clavulanate, as are the cephalosporins (Hugonnet et al, 2009;Ramón-Garcıá et al, 2016). The clinical effectiveness of meropenem is less clear, due to tolerability issues (De Jager et al, 2022), but this has led to an increased effort to find new beta lactams (Gold et al, 2022).…”

Section: New Gyrase Inhibitorsmentioning

confidence: 99%

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

Bhagwat

Deshpande²,

Parish³

2022

Front. Cell. Infect. Microbiol.

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Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and when designing novel regimens. We review a number of different approaches to develop new analogs and drug combinations or improve efficacy of existing drugs that may overcome or delay the appearance of clinical resistance. We also discuss the need to fully characterize mechanisms of resistance and cross- resistance to existing drugs to ensure that novel drugs will be clinically effective.

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Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial

Cited by 23 publications

References 24 publications

Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

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