Therapeutics


Figure 3: Fluorescent microscopy show that E. coliATCC 25922 is largely impermeable to fluorescently-labelled azithromycin or Bocillin. Addition of 8µg/mL SPR741 increased the uptake of azithromycin and increased accumulation of fluorescent Bocillin. Pogliano J. ‘Bacterial Cytological Profiling of SPR741 Mechanism


of Action is Consistent with Membrane Permeabilization that Allows Penetration of Antibiotics into Gram-negative (G-) Bacteria’. ASM Microbe 2016


Figure 4 shows results from a study of the in


vitro efficacy of combinations of SPR741 with con- ventional antibiotics against Escherichia coli (Ec), Klebsiella pneumoniae (Kp), and Acinetobacter baumannii (Ab). Of 35 antibiotics tested, the min- imum inhibitory concentration (MIC) of eight – azithromycin, clarithromycin (CLR), erythromycin (ERY), fusidic acid (FA), mupirocin, retapamulin (RET) rifampicin (RIF) and telithromycin – against Ec and Kp was reduced 32 – 8,000-fold in the pres- ence of 8-16µg/mL SPR741; against Ab, similar potentiation was achieved with CLR, ERY, FA and RIF. SPR741 was able to potentiate antibiotics that are


substrates of the multi-drug efflux pump


AcrAB-TolC, effectively circumventing the pump’s contribution to intrinsic antibiotic resistance. Green arrows indicate that the MIC of the antibi- otic has been reduced to, or below, the Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for susceptibility for this organism/antibiotic combination, or where this information is not available, below the equivalent breakpoint or epidemiological cut-off values (ECOFF) for Staphylococcus spp.


Indirect therapeutics


Instead of killing the bacteria directly, some strate- gies focus on blocking the bacteria’s virulence. For example, Microbiotix, Inc has developed a strategy that interferes with the Type III secretion system of Pseudomonas aeruginosa, a bacteria which pro- duces a toxin that plays a major role in ventilator- assisted pneumonia. Preventing release of the toxin should block disease progression.


12


Biological strategies


The war between the microbes has raged for giga- millennia. No battle is fiercer than the struggle between bacteria and specialised viruses that prey on them called bacteriophage. To release their progeny from inside an infected bacterial cell, phage encode a number of products called lysins that disrupt the bacterial cell wall, rupturing it and killing the bacteria. The idea to use bacteriophage lysins as a medicine has been around for decades, but the advent and success of antibiotics shelved most projects. With the rise of multi-drug resistance, lysins are experiencing a renaissance. ContraFect Corpora- tion, for example, has identified 48 lysins that can directly bind and disrupt the cell wall of Gram-neg- ative bacteria, killing them on contact. The compa- ny’s first bacteriophage-derived lysin has entered clinical trials.


Another biological strategy relies on monoclonal antibodies (mAbs). Just as cancer researchers have successfully engineered antibodies to seek out and kill cancer cells, scientists are now turning those tools toward multi-drug resistant bacteria. Research teams focused on developing novel mAbs against micro-organisms have begun to make progress. In one interesting approach, Visterra Inc developed a monoclonal antibody that specifically targets Pseudomonas, and to which is chemically linked a bactericidal peptide that directly kills the bacteria.


Small molecule discovery


Quite a number of biopharma companies pursue different strategies to discover new antibiotics in the traditional way. Tetraphase Pharmaceuticals


Drug Discovery World Summer 2017


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72