The rapid emergence of antibiotic resistance among pathogenic microorganisms due to misuse has become a serious health problem fostered by researchers to explore new antimicrobial compounds [1]. According to AJ Browne, MG Chipeta, G Haines-Woodhouse, EP Kumaran, BHK Hamadani, S Zaraa, NJ Henry, A Deshpande, RC Reiner and NP Day [2], a 76% increase in antibiotics consumption during the pre-COVID- 19 era, was observed during 18 years, from 2000 to 2018, in low- and middle-income countries, with increased ration of (111%) in North Africa and Middle East region and (116%) in South Asia. Also, there is a gradual rise in antibiotics consumption especially (cephalosporins, penicillins, macrolides, and tetracyclines), among the Globe inhabitants due to the pandemic of COVID − 19 [3]. This dramatic changes in humans life conditions has impacted the enteric pathogenic bacteria as a collateral influence, and led to increased bacterial resistance to antibiotics [4].
By harnessing the potential of actinobacterial natural products, researchers are now uncovering novel ATP synthase inhibitors that could have therapeutic applications. ATP synthase, is a critical enzyme involved in the synthesis of adenosine triphosphate (ATP), and serves as the primary energy source for both prokaryotic and eukaryotic cells. It is, now, being recognized for its diverse functions at the cell surface and within mitochondria. Consequently, this pivotal enzyme complex is gaining recognition as a molecular target for treating different diseases [5]. The inhibition of ATP synthase interferes the energy production and, potentially, impact specific cellular functions. Therefore, exploration of this type of inhibitors represents an emerging field of research [6].
While the discovery and development of ATP synthase inhibitors have been primarily focused on synthetic compounds or natural products from plants ‘Phytochemicals’[7], the investigation of bacteria-derived inhibitors brings forth new possibilities. Various strains of actinobacteria, particularly Streptomyces, are known as potent inhibitors of ATP synthase [8]. Numerous antibiotic-resistance-related scenarios have led to the suggestion of various antibiotic combinations with additional compounds, aiming to restrict the proliferation of bacteria that are resistant to antibiotics. These combinations were initially inspired by ATP synthase inhibitors like resveratrol, oligomycin A, and N,N-dicyclohexylcarbodiimide [6]. These are just a few examples, and many other actinobacterial species may also produce compounds with similar inhibitory properties, highlighting the diverse range of natural sources for potential therapeutic agents targeting ATP synthase. The co-administration of ATP synthase inhibitors with antibiotics increases the susceptibility of antibiotic-resistant bacteria [6]. For example, V Yarlagadda, R Medina and GD Wright [8] has identified Venturicidin A, an ATP synthase inhibitor from Streptomyces sp.. Their results have demonstrated the complementing effect of Venturicidin A with aminoglycoside antibiotics against multidrug resistant (MDR) bacteria.
Micromonospora species are second in line, after Streptomyces, as one of the most important producers of commercially successful secondary bioactive metabolite. According to records, over 88 Micromonospora species recovered from several environments produced various bioactive metabolites [9]. Micromonospora strains are also known for their potential to produce plant growth promoters [10] and various antibiotics including, aminoglycosides, enediynes, and oligosaccharides [11]. For such valuable strains, metagenomics-based approaches, and modern metabolomics-inspired methods greatly help improve access to novel natural product and comprehensively exploit its full potential [12].
Our previous work on Micromonospora strains F58, 65SH, S56, isolated from different Egyptian environments, indicated their promising bioactivities [13]. Therfore, this study was designed to evaluate the antimicrobial potential secondary metabolites from the Micromonospora strains; and elucidate the chemical constituents with high minimum inhibitory concentration against selected strains of the multidrug resistant (MDR) enteric pathogens. We used a specific molecular modeling technique and metabolomics to identify the high-potential compounds and some of their activity mechanisms to inhibit ATP synthase.