Ifeanyichukwu Emmanuel Eke

All Publications

• Defining the mechanism of action of the nitrofuranyl piperazine HC2210 against Mycobacterium abscessus. npj antimicrobials and resistance Eke, I. E., Abdalla, B. J., Soverina, S., Olive, A. J., Cicchetti, N., Carey, A. F., Abramovitch, R. B. 2025; 3 (1): 55

  Abstract

  Mycobacterium abscessus (Mab) has intrinsic resistance to diverse classes of antibiotics, making this non-tuberculous mycobacterial (NTM) infection challenging to treat. Three nitrofuranyl piperazines-HC2209, HC2210, and HC2211-were previously reported to be active against M. tuberculosis (Mtb). Here we report that HC2210 is also active against Mab and define its mechanisms of action. HC2210 is about fivefold more potent than amikacin, is active against multidrug-resistant Mab clinical isolates, and synergizes with bedaquiline, clarithromycin, and meropenem. Isolation of resistant mutants supports that HC2210 requires cofactor F420, although an F420-dependent activating nitroreductase could not be identified. Additionally, resistance mutations in glycerol kinase (glpK) were selected for with HC2210. Transcriptional profiling shows that HC2210 modulates the expression of Mab genes associated with oxidative stress and lipid metabolism, a response that is distinct from Mtb. These findings demonstrate the potential for developing the HC2210 series as a new drug to treat Mab infections.

  View details for DOI 10.1038/s44259-025-00124-0

  View details for PubMedID 40517180

• Identification of covalent inhibitors of Staphylococcus aureus serine hydrolases important for virulence and biofilm formation. Nature communications Upadhyay, T., Woods, E. C., Dela Ahator, S., Julin, K., Faucher, F. F., Uddin, M. J., Hollander, M. J., Pedowitz, N. J., Abegg, D., Hammond, I., Eke, I. E., Wang, S., Chen, S., Bennett, J. M., Jo, J., Lentz, C. S., Adibekian, A., Fellner, M., Bogyo, M. 2025; 16 (1): 5046

  Abstract

  Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide. New tools are needed to both image and treat this pathogen. We previously identified a group of S. aureus serine hydrolases (Fphs), which regulate aspects of virulence and lipid metabolism. However, due to high structural and functional similarities, it remains challenging to distinguish the specific roles of members of this family. Here, we apply a high-throughput screening approach using a library of covalent electrophiles to identify inhibitors for FphB, FphE, and FphH. We identify selective covalent inhibitors for each target without the need for extensive medicinal chemistry optimization. Structural and biochemical analysis identify novel binding modes for several of the inhibitors. Functional studies using the inhibitors suggest that all three hydrolases likely play distinct functional roles in biofilm formation and virulence. This approach has the potential to be applied to target hydrolases in other diverse pathogens or higher eukaryotes.

  View details for DOI 10.1038/s41467-025-60367-3

  View details for PubMedID 40447595

  View details for PubMedCentralID 9882747

• Genetic and Cheminformatic Characterization of Mycobacterium tuberculosis Inhibitors Discovered in the Molecular Libraries Small Molecule Repository. ACS infectious diseases Eke, I. E., Williams, J. T., Abramovitch, R. B. 2025

  Abstract

  High-throughput screening (HTS) of small molecules is a starting point for many drug development pipelines, including tuberculosis. These screens often result in multiple hits whose mechanisms of action remain unknown. From our initial HTS of the Molecular Libraries Small Molecule Repository (MLSMR), we cherry-picked 935 compounds that inhibited the growth of Mycobacterium tuberculosis and set out to provide an early assessment of their antimycobacterial properties and mechanism of action. To characterize the MLSMR Mtb growth inhibitors, a combination of cheminformatics and targeted mutant screening against mutants in katG, hadAB, and a mixed pool of mmpL3 mutants was used to characterize the hits. As a validation of this approach, we identified 101 isoniazid analogs that predictably lose all their antimycobacterial activities against the katG mutant. Interestingly, eight isoniazid analogs retain part of their activity against the mutant, suggesting an alternative KatG-independent mechanism. This approach also identified new compounds belonging to already known scaffolds that target HadAB or MmpL3. Additionally, we explored the nitro-containing compounds in our data set and discovered nitrofuranyl benzothiazoles that show enhanced activity against the mmpL3 and katG mutants, a phenomenon known as collateral sensitivity. Overall, this study will serve as an important resource for further follow-up studies of antitubercular small molecules in the MLSMR library and provide a well-characterized training set for artificial intelligence-driven antimycobacterial drug discovery.

  View details for DOI 10.1021/acsinfecdis.4c00936

  View details for PubMedID 40131268

• Functions of nitroreductases in mycobacterial physiology and drug susceptibility. Journal of bacteriology Eke, I. E., Abramovitch, R. B. 2025: e0032624

  Abstract

  Tuberculosis is a respiratory infection that is caused by members of the Mycobacterium tuberculosis complex, with M. tuberculosis (Mtb) being the predominant cause of the disease in humans. The approval of pretomanid and delamanid, two nitroimidazole-based compounds, for the treatment of tuberculosis encourages the development of more nitro-containing drugs that target Mtb. Similar to the nitroimidazoles, many antimycobacterial nitro-containing scaffolds are prodrugs that require reductive activation into metabolites that inhibit the growth of the pathogen. This reductive activation is mediated by mycobacterial nitroreductases, leading to the hypothesis that these nitroreductases contribute to the specificity of the nitro prodrugs for mycobacteria. In addition to their prodrug-activating activities, these nitroreductases have different native activities that support the growth of the bacteria. This review summarizes the activities of different mycobacterial nitroreductases with respect to their activation of different nitro prodrugs and highlights their physiological functions in the bacteria.

  View details for DOI 10.1128/jb.00326-24

  View details for PubMedID 39772630

• Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and in vivo efficacy. Antimicrobial agents and chemotherapy Eke, I. E., Williams, J. T., Haiderer, E. R., Albrecht, V. J., Murdoch, H. M., Abdalla, B. J., Abramovitch, R. B. 2023; 67 (9): e0047423

  Abstract

  Nitro-containing compounds have emerged as important agents in the control of tuberculosis (TB). From a whole-cell high-throughput screen for Mycobacterium tuberculosis (Mtb) growth inhibitors, 10 nitro-containing compounds were prioritized for characterization and mechanism of action studies. HC2209, HC2210, and HC2211 are nitrofuran-based prodrugs that need the cofactor F420 machinery for activation. Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F420-dependent reductase for activation. These nitrofurans also differ from pretomanid in their potent activity against Mycobacterium abscessus. Four dinitrobenzamides (HC2217, HC2226, HC2238, and HC2239) and a nitrofuran (HC2250) are proposed to be inhibitors of decaprenyl-phosphoryl-ribose 2'-epimerase 1 (DprE1), based on isolation of resistant mutations in dprE1. Unlike other DprE1 inhibitors, HC2250 was found to be potent against non-replicating persistent bacteria, suggesting additional targets. Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb in vitro, but a proposed mechanism of action could not be defined. In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.

  View details for DOI 10.1128/aac.00474-23

  View details for PubMedID 37610224

  View details for PubMedCentralID PMC10508139

• Cattle manure as a sustainable bioenergy source: Prospects and environmental impacts of its utilization as a major feedstock in Nigeria BIORESOURCE TECHNOLOGY REPORTS Onwosi, C. O., Ozoegwu, C. G., Nwagu, T. N., Nwobodo, T. N., Eke, I. E., Igbokwe, V. C., Ugwuoji, E. T., Ugwuodo, C. J. 2022; 19

  View details for DOI 10.1016/j.biteb.2022.101151

  View details for Web of Science ID 001209007700016

• Principal component analysis reveals microbial biomass carbon as an effective bioindicator of health status of petroleum-polluted agricultural soil. Environmental technology Onwosi, C. O., Odimba, J. N., Igbokwe, V. C., Nduka, F. O., Nwagu, T. N., Aneke, C. J., Eke, I. E. 2020; 41 (24): 3178-3190

  Abstract

  We investigated a number of microbiological activities in the soil to serve as biomonitoring tools in assessing the ecotoxicity of diesel-contaminated soil samples during the different periods of bioremediation. Sawdust was used as the biostimulant for the biodegradation of artificial diesel-polluted soil samples. Soil microbial population, soil microbial enzymatic activities (catalase, lipase, dehydrogenase, urease, phosphatase and β-glucosidase), soil microbial biomass carbon (MBC), nitrogen (MBN) and phosphorus (MBP), soil microbial respirometric index and total petroleum hydrocarbon (TPH) concentration were monitored to evaluate the efficiency of the bioremediation process. After a period of 56 d, total petroleum hydrocarbon content reduced from 14,221 to 270 mg/kg. The parameter estimation using the nth-order kinetic model revealed that the first-order rate constants (k) for TPH removal were 4.417 d-1 and 0.2670 d-1 for sawdust-amended and unamended soil, respectively. This implied that, the sawdust amendment resulted in reaction rate 16.5 times faster than unamended soil. Thus, the biological indicators were generally more pronounced in biostimulated soil than the attenuated soil. However, to evaluate the efficiency of the sawdust-assisted bioremediation, principal component analysis, which was used in selecting the most sensitive bioindicators. It was observed that microbial biomass carbon, catalase, lipase and dehydrogenase were the most responsive bioparameters. A positive relationship between TPH removal and the four most sensitive bioparameters suggests that the use of four biological activities have proven to be effective monitoring tools for evaluating the efficiency of a bioremediation strategy.

  View details for DOI 10.1080/09593330.2019.1603252

  View details for PubMedID 30982397

• Towards effective management of digester dysfunction during anaerobic treatment processes RENEWABLE & SUSTAINABLE ENERGY REVIEWS Onwosi, C. O., Eke, I. E., Igbokwe, V. C., Odimba, J. N., Ndukwe, J. K., Chukwu, K. O., Aliyu, G. O., Nwagu, T. N. 2019; 116

  View details for DOI 10.1016/j.rser.2019.109424

  View details for Web of Science ID 000523392400025

• Dermatophytes and dermatophytosis in the eastern and southern parts of Africa. Medical mycology Nweze, E. I., Eke, I. E. 2018; 56 (1): 13-28

  Abstract

  Dermatophytosis is currently a disease of global importance and a public health burden. It is caused by dermatophytes, which attack and grow on dead animal keratin. Dermatophytes belong to three genera, namely, Epidermophyton, Microsporum, and Trichophyton. The predominant clinical forms and causative agents vary from one region of the world to another. Poor socioeconomic status, high population densities, and poor sanitary conditions are some of the factors responsible for the high prevalence of dermatophytosis in many developing countries, which include countries in southern and eastern Africa, the focus of this review. To the best of our knowledge, there is currently no review article on published findings on dermatophytosis in the eastern and southern parts of Africa. This information will be of interest to the medical and research community since the world has become a global village. This review covers published research findings in eastern and southern regions of Africa until this date. The countries covered in the current review include Kenya, Ethiopia, Tanzania, South Africa, Mozambique, Madagascar, Malawi, Rwanda, Burundi, Uganda, Zambia, Zimbabwe, and Botswana. T. violaceum is the most common human etiological agent in all the countries under review with prevalence ranging from 56.7% to 95%, except for Madagascar (M. langeronii, reclassified as M. audouinii), Uganda (M. gypseum) and Malawi (M. audouinii). Tinea capitis was the most clinical type, followed by tinea corporis. Etiological agents of animal dermatophytoses were variable in the countries where they were reported. Major risk factors for dermatophytoses are age, climatic, and socioeconomic factors.

  View details for DOI 10.1093/mmy/myx025

  View details for PubMedID 28419352

• Composting technology in waste stabilization: On the methods, challenges and future prospects. Journal of environmental management Onwosi, C. O., Igbokwe, V. C., Odimba, J. N., Eke, I. E., Nwankwoala, M. O., Iroh, I. N., Ezeogu, L. I. 2017; 190: 140-157

  Abstract

  Composting technology has become invaluable in stabilization of municipal waste due to its environmental compatibility. In this review, different types of composting methods reportedly applied in waste management were explored. Further to that, the major factors such as temperature, pH, C/N ratio, moisture, particle size that have been considered relevant in the monitoring of the composting process were elucidated. Relevant strategies to improve and optimize process effectiveness were also addressed. However, during composting, some challenges such as leachate generation, gas emission and lack of uniformity in assessing maturity indices are imminent. Here in, these challenges were properly addressed and some strategies towards ameliorating them were proffered. Finally, we highlighted some recent technologies that could improve composting.

  View details for DOI 10.1016/j.jenvman.2016.12.051

  View details for PubMedID 28040590

• Dermatophytosis in northern Africa. Mycoses Nweze, E. I., Eke, I. 2016; 59 (3): 137-44

  Abstract

  Infections caused by dermatophytes are a global problem and a major public health burden in the world today. In Africa, especially in the northern geographical zone, dermatophytic infections are being reported at an alarming rate. This is mostly because of some local but unique cultural practices, socioeconomic and environmental conditions, lack of reliable diagnostic personnel and facilities and ineffective treatment. Interestingly, the pathogen spectrum and the clinical manifestation are most times different from what is seen in other continents. Several epidemiological studies have been performed on the incidence and aetiology of dermatophytoses in northern Africa. However, there is currently no review article with up-to-date information on the relevant findings reported so far in this region. This information is necessary for clinicians who treat dermatophytic infections all over the world since agents of dermatophytes are no longer restricted because of the rapid mobility of humans from one part of the world to another. Moreover, the epidemiology of dermatophytoses is known to change over time, thus requiring the update of information from time to time. A review of relevant studies published on dermatophytoses in northern Africa is presented. This covers all of old Sudan, Algeria, Egypt, Libya, Tunisia and Morocco.

  View details for DOI 10.1111/myc.12447

  View details for PubMedID 26692117