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. 2021 Mar 8;12(4):579–584. doi: 10.1021/acsmedchemlett.0c00632

Impact of Mitochondrial Targeting Antibiotics on Mitochondrial Function and Proliferation of Cancer Cells

Edward J Cochrane ‡, James Hulit †, Franz P Lagasse ‡, Tanguy Lechertier †, Brett Stevenson ‡, Corina Tudor †, Diana Trebicka †, Tim Sparey †, Andrew J Ratcliffe †,*
PMCID: PMC8040039  PMID: 33859798

Abstract

graphic file with name ml0c00632_0015.jpg

Some marketed antibiotics can cause mitochondria dysfunction via inhibition of the mitochondrial translation process. There is great interest in exploiting such effects within a cancer setting. To enhance accumulation of antibiotics within the mitochondria of cancer cells, and therefore delivery of a greater potency payload, a mitochondrial targeting group in the form of a triphenylphosphonium (TPP) cation was appended via an alkyl chain length consisting of 7 to 11 carbons to the ribosomal antibiotics azithromycin and doxycycline. Using MDA-MB-231 cells, the effects of each subseries on mitochondrial translation, mitochondrial bioenergetics, and cell viability are described.

Keywords: Mitochondrial targeting, triphenylphosphonium conjugate, delocalized cation, antibiotics, cancer cell proliferation

The electron transport chain (ETC) system plays a key role in maintaining the energy status of the cell to support physiological functions, such as proliferation and survival. Critical synthesis of 13 subunit components of the ETC complexes I, III, IV, and V are under the control of the mitochondrial translation system. In contrast, all complex II subunits are encoded by the nuclear DNA and imported into the mitochondria. It is generally accepted that mitochondria evolved from alpha-proteobacteria through evolutionary pressure. In line with this thinking, several recent papers have highlighted the observation that antibiotics, in particular the ribosomal targeting class of drugs, can interfere with the mitochondrial translation process, leading to mitochondrial dysfunction and potential toxicological consequences.1−3

From a cancer perspective, there is growing interest in exploiting such mitochondrial dysfunction to target the bioenergetic metabolism of cancer cells and repurpose antibiotics as anticancer drugs.4−6 To this end, tigecycline has been shown to eradicate leukemic stem cells.7 Moreover, in renal cell carcinoma (RCC), ovarian, thyroid carcinoma, and hepatocellular carcinoma (HCC) mouse xenograft models, dosing with tigecycline in combination with an appropriate standard of care therapeutic has shown enhanced efficacy.8−11 As a standalone agent, tigecycline is being pursued as a therapeutic strategy to treat human acute myeloid leukemia.12

Specific targeting of drugs to the mitochondria has become an area of great interest, where delivery of a more precise and effective payload can offer therapeutic advantages. One strategy is centered on linking of the bioactive to a triphenylphosphonium (TPP) cation, where a combination of the lipophilicity of the TPP cation coupled with its extensive positive charge delocalization favors transport and accumulation across membranes of high negative potential, as found at the mitochondrial inner membrane.13 Such an approach has been applied to the therapeutic targeting of tumor mitochondria.14

The present work describes our findings on the effect at the mitochondrial level of installing a TPP cation within a series of azithromycin 1–5 and doxycycline 6–10 analogues, where the alkyl linker length connecting the TPP cation to the antibiotic is varied (Figure 1). Azithromycin and doxycycline antibiotics were chosen as representative examples of interactions with the large and small bacterial ribosomal subunits, respectively.

Figure 1.

Figure 1

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Design of TPP-based azithromycin and doxycycline analogues.

In seeking to impart mitochondrial ribosomal binding, the linker connecting the TPP cation to the antibiotic was attached at positions deemed away from the critical azithromycin and doxycycline binding regions established for bacterial ribosomes.15,16 In line with this thinking, and taking into account consideration of synthetic chemistry tractability, the nitrogen of the azithromycin 15-membered macrocyclic ring and aromatic carbon ortho to the phenol group in doxycycline served as attachment sites. Amide functionality was employed to forge the linker-antibiotic connection.

The compounds were synthesized using amide-coupling-based reactions between the requisite TPP cation carboxylic acids 11–15 and the appropriate azithromycin amine 16 or doxycycline amine 17 (Scheme 1). Details are provided in SI.

Scheme 1. Synthesis of TPP-Based Azithromycin and Doxycycline Analogues.

Scheme 1

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Compounds 1–5 and 6–10 at 1 μM were incubated with GFP-labeled MDA-MB-231 cells under low oxygen (3% O2) conditions. Azithromycin at 30 μM and doxycycline at 25 μM were included as reference points. After 72 h, mitochondrial translation was indirectly analyzed through cytochrome c oxidase (COX1) expression, COX1 representing a subunit of the mitochondrial respiratory complex IV and translated by mitochondrial ribosomes.

Within the azithromycin-TPP subseries, 1 imparted a strong inhibition of COX1 protein expression, which decreased in a stepwise manner on traversing the linker length to 3 (Figure 2). Both 4 and 5 followed 3 in delivering no inhibition at 1 μM. Indeed, for reasons that are unclear, the 8-carbon alkyl chain analogue 4 appeared to potentiate COX1 protein expression level compared to control levels.

Figure 2.

Figure 2

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Azithromycin-TPP subseries and inhibition of mitochondrial COX1 protein expression in GFP-labeled MDA-MB-231 cells under low oxygen (3% O2) conditions at 1 μM. (a) Representative image of COX1 and ACTIN levels observed in Western-blot. (b) Quantification of protein levels normalized to DMSO. Bar chart represents protein level of COX1 ± S.D., n = 2–3, ** p < 0.01, student’s t test.

The alkyl linker length relationship across the subseries may reflect entry efficiency of the TPP-derived compounds for accumulation within the mitochondria. Similar observations have been noted within an alkyl series of mitochondria-targeted TPP analogues of metformin, where in this case, the longer 10-carbon alkyl chain proved optimal vs shorter chain length variants at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC).17 Azithromycin at 30 μM only led to ≈30% inhibition of COX1 protein expression level, lending support to the design concept and potency enhancing effect of appendage of an appropriately tethered TPP cation.

Within the doxycycline-TPP subseries, a different SAR picture emerges. Although the most potent inhibitory activity resides within the 11-carbon alkyl analogue 6 (as observed within the azithromycin-TPP subseries), the reduction in potency on shortening the chain length is less dramatic (Figure 3).

Figure 3.

Figure 3

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Doxycycline-TPP subseries and inhibition of mitochondrial COX1 protein expression in GFP-labeled MDA-MB-231 cells under low oxygen (3% O2) conditions at 1 μM. (a) Representative image of COX1 and ACTIN levels observed in western-blot. (b) Quantification of protein levels normalized to DMSO. Bar chart represents protein level of COX1 ± S.D., n = 2–4, * p < 0.05 and ** p < 0.01, student’s t test.

In contrast to the lack of activity with the azithromycin-TPP 9-carbon alkyl bearing compound 3, the matched doxycycline analogue 8 proved to elicit ≈50% reduction in COX1 protein expression level. Potentiation of COX1 protein expression level compared with control was also noted but in this case linked with the 7-carbon alkyl chain analogue 10 (Figure 3). Doxycycline at 25 μM delivered a similar level of inhibition as for azithromycin, again underpinning the TPP design principles.

Compound profiling at 1 μM was chosen to deliver the dynamic range on COX1 expression to allow comparison of the subseries in relation to linker length. The different SAR patterns between the azithromycin-TPP and doxycycline-TPP subseries clearly demonstrates the influence of the different antibiotics employed. Although the nature of the antibiotic may influence entry efficiency of the TPP conjugate within the mitochondrion, a further factor for consideration in dictating the SAR may reside in the subtleties of different binding interactions of the azithromycin-TPP and doxycycline-TPP subseries at their respective binding sites within the large and small subunits of the mitochondrial ribosomes.

To ascertain the functional effects on mitochondrial respiration, the oxygen consumption rate (OCR), which is an indicator of respiratory chain activity and the potential capacity of the cells to generate ATP, was measured using the Seahorse XFe96 Analyzer.

Compounds 1–5 and 6–10 at 1 μM were incubated with GFP-labeled MDA-MB-231 cells under atmospheric O2 for 88 h prior to respiratory analysis. OCR was measured in the absence (the first 3 measurements) and presence (measurements 4–12) of oligomycin (OLI), carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and antimycin A and rotenone combination (A&R).

Compound 1, bearing the 11-carbon alkyl chain, strongly suppressed mitochondria respiration, followed by moderate effects with the 10-carbon alkyl chain analogue 2 (Figure 4). In contrast, the shorter chain compounds 3, 4, and 5 elicited weak to no effects (Figure 4). Azithromycin at 30 μM only gave a moderate effect against maximal respiration.

Figure 4.

Figure 4

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Azithromycin-TPP subseries and inhibition of OCR after 88 h incubation prior to respiratory analysis. (a) Seahorse plot. OLI, FCCP, and A&R were sequentially injected into the wells at the time indicated by the dotted lines. Basal OCR is calculated as the first 3 measurements. Maximal OCR is calculated as the 3 measurements after FCCP injection. Graphs show a representative experiment. (b) Quantification of basal and maximal respiration represented with the bar chart ± S.D., n = 2–6, ** p < 0.01, student’s t test.

Within the azithromycin-TPP subseries, the rank order of inhibition of basal and maximal respiration generally mirrored the compound inhibitory effects observed on COX1 expression (Figure 2).

Hydrophobic TPP cation 10–12 alkyl carbon linker conjugates containing no bioactive cargo at concentrations of 1 μM and below have been shown by several studies to cause detrimental effects on mitochondrial bioenergetics through uncoupling of oxidative phosphorylation via significant proton leakage and disruption of the membrane potential.18−20 Cellular uptake of the compounds is rapid, and the effects are typically observed in minutes under acute exposure conditions, persisting during chronic exposure.21

With compound 1 at 1 μM, no effects on basal or maximal respiration or proton leakage were observed in an acute setting with an extended 60 min incubation, lending support to strong inhibition of mitochondrial protein synthesis after 88 h incubation being the key driver associated with the observed dramatic reduction in OCR, rather than effects potentially caused by the TPP cation moiety (Figure 5).

Figure 5.

Figure 5

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(a) Seahorse plot of compound 1 after 60 min incubation prior to respiratory analysis. OLI, FCCP, and A&R were sequentially injected into the wells at the time indicated by the dotted lines. Basal OCR is calculated as the first 3 measurements. Maximal OCR is calculated as the 3 measurements after FCCP injection. (b) Bar graph of proton leakage n = 2.

Further evidence is provided by compound 18, a close analogue of compound 1, which lacks the cladinosyl and desosaminyl sugars of azithromycin. From azithromycin bacterial ribosome structural studies, the presence of the azithromycin sugars is deemed important for ribosomal binding and inhibition.15

Compound 18 was synthesized using the same procedure as for compound 1 but using amine 19 (Scheme 2).

Scheme 2. Synthesis of Compound 18.

Scheme 2

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An acute 60 min exposure of compound 18 at 1 μM in GFP-labeled MDA-MB-231 cells gave no detrimental effects on mitochondrial bioenergetics [data not shown]. After 88 h, no effects were observed on basal respiration, with only a small reduction of maximum respiration. This is in distinct contrast to compound 1 at 1 μM, where significant decreases in both parameters were observed (Figure 6). In addition little impact was noted on proton leakage with either compound (Figure 6).

Figure 6.

Figure 6

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(a) Seahorse plot of compound 18 and 1 after 88 h incubation prior to respiratory analysis. OLI, FCCP, and A&R were sequentially injected into the wells at the time indicated by the dotted lines. Basal OCR is calculated as the first 3 measurements. Maximal OCR is calculated as the 3 measurements after FCCP injection. (b) Quantification of basal and maximal respiration and proton leakage represented in bar chart ± S.D., n = 2, * p < 0.05, ** p < 0.01, student’s t test.

Within the doxycycline-TPP subseries the 11, 10, and 9-carbon alkyl chain analogues 6, 7, and 8 appeared to elicit a similar level of inhibition of basal and maximal respiration (Figure 7), in line with their similar observed effects on inhibition of COX1 protein expression (Figure 3). There was a reduced response to compound 9, which mirrored the diminished inhibitory effect observed on COX1 protein expression. In contrast, compound 10 failed to elicit a response on OCR, in alignment with any noted loss of COX1 expression.

Figure 7.

Figure 7

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Doxycycline-TPP subseries and inhibition of OCR after 88 h incubation prior to respiratory analysis. (a) Seahorse plot. OLI, FCCP, and A&R were sequentially injected into the wells at the time indicated by the dotted lines. Basal OCR is calculated as the first 3 measurements. Maximal OCR is calculated as the 3 measurements after FCCP injection. Graphs show a representative experiment. (b) Quantification of basal and maximal respiration represented in bar chart ± S.D., n = 2–6, * p < 0.05, ** p < 0.01, student’s t test.

To investigate if the effects on mitochondrial respiration translated to cell-based viability, GFP-labeled MDA-MB-231 cells were incubated with compounds 1–5 and 6–10 up to 5 μM under conditions of low oxygen (3% O2). Real-time cell growth was monitored in an Incucyte Zoom system, with EC50s generated after 108 h. Within the azithromycin-TPP subseries compound 1 bearing the 11-carbon alkyl chain elicited potent sub-μM inhibition (Figures 8 and 10), in line with observed effects on mitochondrial respiration. Shortening the linker length stepwise across the subseries led to a reduction in cell potency and increase in EC50. Compounds 2 and 3 delivered low μM inhibition, while compounds 4 and 5 failed to register any inhibition at the top concentration of 5 μM employed (Figures 8 and 10). The SAR observed follows the general activity relationship noted from mitochondrial respiration studies (Figure 4).

Figure 8.

Figure 8

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Azithromycin-TPP subseries and inhibition of proliferation of GFP-labeled MDA-MB-231 cells under low oxygen (3% O2) conditions. n = 3.

Figure 10.

Figure 10

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EC50 values of azithromycin-TPP subseries (compounds 1–3) and doxycycline-TPP subseries (compounds 6–10). Bar chart represents the average EC value ± S.D., n = 3, * p < 0.05, ** p < 0.01, student’s t test.

Within the doxycycline-TPP subseries, all the compounds delivered an EC50 (Figures 9 and 10). The most potent corresponded to compound 6 containing the 11-carbon alkyl chain. The sub-μM potency of the compound matched that observed with the equivalent azithromycin-TPP compound 1 (Figure 10). Stepwise shortening of the linker length from compound 6 through to compound 10 mirrored a gradual reduction in EC50. Considering the different assay conditions (test concentration and % O2), a cross comparison of the mitochondrial respiration of the doxycycline-TPP compounds 6 to 10 to corresponding cell-based viability data (comparison of Figure 7 to 10) suggest some SAR concordance. Both compounds 6 and 7 exhibit similar profiles across both assay formats, while the shorter linked compounds 9 and 10 experience reduced potency and EC50 shifts to the right, aligned with reduced mitochondrial targeting activity. On the basis of its mitochondrial OCR profile, compound 8 would be predicted to be slightly more potent than observed in the cell viability assay. Exact reasons for this are unclear and await further investigation.

Figure 9.

Figure 9

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Doxycycline-TPP subseries and inhibition of proliferation of GFP-labeled MDA-MB-231 cells under low oxygen (3% O2) conditions. n = 3.

Interestingly, comparison of cell viability data of the matched compound pairs 4 and 9, and 5 and 10, which contain the same linker length but different attached antibiotics, again highlight the impact of the different antibiotics used. Although trends between the two subseries are evident, direct transfer of SAR from one series to another is not.

In conclusion, the data presented supports the concept that the potency of antibiotics at causing mitochondrial dysfunction in cancer cells can be increased by appendage of an appropriately tethered TPP cation. The extent of the potency enhancement is dictated not only by the length of alkyl chain tether utilized but also by the class of ribosomal antibiotic employed. More in-depth studies with the 11-carbon alkyl chain bearing compounds 1 and 6 will be reported in due course.

Acknowledgments

The authors would like to thank Mrs Rachel Neary (Sygnature DMPK & Physical Sciences group) for generation of the high-resolution mass spectral data and Dr Alexandre Froidbise (Evotec) for synthesis of 10.

Glossary

ABBREVIATIONS

ETC

electron transport chain

RCC

renal cell carcinoma

HCC

hepatocellular carcinoma

PDAC

pancreatic ductal adenocarcinoma

TPP

triphenylphosphonium

COX1

cytochrome c oxidase subunit I

SAR

structural activity relationship

DMSO

dimethyl sulfoxide

OCR

oxygen consumption rate

FCCP

carbonyl cyanide-p-trifluoromethoxyphenylhydrazone

OLI

oligomycin

A

antimycin

R

rotenone

GFP

green fluorescent protein

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00632.

  • Synthetic protocols for compounds 1 to 10 and 18; protocols for evaluation of mitochondrial translation, mitochondrial respiration, and cell viability (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This research was financed by the Rising Tide Foundation for Clinical Cancer Research, Herrenacker 15, CH-8200, Schaffhausen, Switzerland.

The authors declare no competing financial interest.

Supplementary Material

ml0c00632_si_001.pdf (700.4KB, pdf)

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Associated Data

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Supplementary Materials

ml0c00632_si_001.pdf (700.4KB, pdf)

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