TXA-709 –  New Kid on the Block

When searching for FtsZ inhibitors on PubMed, there are 187 hits. When narrowing down the search looking for clinical trials only, there are none.

Taxis Pharmaceuticals obtained QIDP status for its candidate drug TXA-709 in late 2016 and it is still in preclinical testing. The drug’s target, bacterial replication machinery that forms the Z-ring, is novel and has real potential as all bacteria replicate by binary fission and must generate a cell division wall to split apart. It would seem that attacking this essential step in bacterial cell division would not only arrest bacterial multiplication and achieve bacterial stasis, but also bactericidal activity due to autolysis from frustrated reproduction [1]. This was already demonstrated in experimental studies with MSSA strains.[2]

Key to the potential of any new antibacterial drug is target selection: how essential is this target for replication and critical bacterial life processes? Is it highly conserved and found in most species? Can it be bypassed and have bacteria found alternate routes circumventing a blocked enzymatic step?  Are mutations of the target lethal?

Other questions – more generic in nature – deal with accessibility of target for a drug, binding affinity, and the usual defense mechanism of efflux and drug degradation/inactivation.

From rudimentary information available on TXA-709, we cannot answer all these questions. We are told that the drug is meant to be developed as an MRSA agent. Our first reaction: Why? Is this the only pathogen susceptible? Are we dealing here again with a very narrow-spectrum drug, the likes and fates of which are not so promising? For Gram-positives, associations with FabI inhibitors resurface, for Gram-negatives, flash-backs of LpxC and POL-7080.

Regarding TXA-709 specifically, the overarching question is: do we really need another MRSA drug with a very narrow spectrum in ABSSSI and maybe in an additional application?

The answer is an unquestionable and unconditional YES, WE DO. The recent batch of approved anti-staph and anti-MRSA drugs are all of the same mold, like glycopeptide structures telavancin, oritavancin, dalbavancin and daptomycin, and oxazolidinone congeners linezolid and tedizolid. MRSA β-lactams ceftaroline and ceftibiprole are just that, β-lactams.

In addition, we have a few less reliable older stand-bys, TMP/SMX, tetracyclines and macrolides. There are also some drugs with MRSA activity that are in development and still have to prove their metal. One of them, solithromycin, just hit a slick spot and is currently in intensive care, so to speak.

Hence, all our workhorse anti-MRSA drugs come from only 3 drug classes. If TXA-709 and its active component, TXA-707, make it to the market as new IV and PO MRSA drugs, we shall be anxious to use them. And so should you. We fully support FDA’s decision to grant QIDP status to this new kid on the block.

A thumbs-up to TXA-709, and by analogy, to FabI inhibitor Debio-1450 and the peptidomimetic brilacidin, all representing different compounds as far as chemistry and MoA are concerned.

TXA-709 does not work in Gram-negatives because of efflux.Taxis Pharma is working on specific efflux inhibitors to broaden the spectrum of TXA-709. A reasonable thing to do but don’t hold your breath for one to materialize soon

Not all looks golden for TXA-709, of course. Obviously, it would be nice if activity were broader than just MRSA, including other Gram-positives perhaps or even Gram-negatives. However, enterococci and streptococci were resistant to a TXA-709 analogue studied by Taxis [3]. Activity against S. epidermidis is useful, activity against B. subtilis not so much [4]. The company is working on efflux inhibitors as the drug is shuttled out of Gram-negative bacteria rendering it ineffective. A recent publication makes a case for combination therapy against MRSA with cefdinir; this cephalosporin provided synergy and reduced MIC values by a factor of 3.[5]

On the positive side, oral and IV formulations both worked well in a peritonitis model, and cytochrome inhibition seems not to occur with TXA-709.

 

References
[1] For a nice and easy explanation of bacterial cell division and the role of FtsZ see: http://web.expasy.org/spotlight/back_issues/171
[2] M Kaul. TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus. AAC 59:4845–4855. doi:10.1128/AAC.00708-15
[3] M Kaul.  Enterococcal and streptococcal resistance to PC190723 and related compounds: Molecular insights from a FtsZ mutational analysis. Biochimie 2013. 95, 10: 1880
[4] http://www.slideshare.net/NhiHin/ftsz-a-promising-and-novel-antibiotic-target
[5] M Kaul. Combining the FtsZ-Targeting Prodrug TXA709 and the Cephalosporin Cefdinir Confers Synergy and Reduces the Frequency of Resistance in Methicillin-Resistant Staphylococcus aureus. AAC 60:4290 –4296. doi:10.1128/AAC.00613-16.

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