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Fulltext Evaluation of fortimicin antibiotic combinations against MDR Pseudomonas aeruginosa and resistome analysis of a whole genome sequenced pan-drug resistant isolate

Kamel NA, Tohamy ST, Alshahrani MY, Aboshanab KM

BMC Microbiol, 2024 May 14;24(1):164.
PMID: 38745145 DOI: 10.1186/s12866-024-03316-2

BACKGROUND: Multidrug-resistant (MDR) P. aeruginosa is a rising public health concern, challenging the treatment of such a ubiquitous pathogen with monotherapeutic anti-pseudomonal agents. Worryingly, its genome plasticity contributes to the emergence of P. aeruginosa expressing different resistant phenotypes and is now responsible for notable epidemics within hospital settings. Considering this, we aimed to evaluate the synergistic combination of fortimicin with other traditional anti-pseudomonal agents and to analyze the resistome of pan-drug resistant (PDR) isolate.
METHODS: Standard methods were used for analyzing the antimicrobial susceptibility tests. The checkerboard technique was used for the in vitro assessment of fortimicin antibiotic combinations against 51 MDR P. aeruginosa and whole genome sequencing was used to determine the resistome of PDR isolate.
RESULTS: Out of 51 MDR P. aeruginosa, the highest synergistic effect was recorded for a combination of fortimicin with β-lactam group as meropenem, ceftazidime, and aztreonam at 71%, 59% and 43%, respectively. Of note, 56.8%, 39.2%, and 37.2% of the tested MDR isolates that had synergistic effects were also resistant to meropenem, ceftazidime, and aztreonam, respectively. The highest additive effects were recorded for combining fortimicin with amikacin (69%) and cefepime (44%) against MDR P. aeruginosa. Resistome analysis of the PDR isolate reflected its association with the antibiotic resistance phenotype. It ensured the presence of a wide variety of antibiotic-resistant genes (β-lactamases, aminoglycosides modifying enzymes, and efflux pump), rendering the isolate resistant to all clinically relevant anti-pseudomonal agents.
CONCLUSION: Fortimicin in combination with classical anti-pseudomonal agents had shown promising synergistic activity against MDR P. aeruginosa. Resistome profiling of PDR P. aeruginosa enhanced the rapid identification of antibiotic resistance genes that are likely linked to the appearance of this resistant phenotype and may pave the way to tackle antimicrobial resistance issues shortly.
Central composite design for optimizing istamycin production by Streptomyces tenjimariensis

Gomaa FAM, Selim HMRM, Alshahrani MY, Aboshanab KM

World J Microbiol Biotechnol, 2024 Sep 09;40(10):316.
PMID: 39249607 DOI: 10.1007/s11274-024-04118-4

Istamycins (ISMs) are 2-deoxyfortamine-containing aminoglycoside antibiotics (AGAs) produced by Streptomyces tenjimariensis ATCC 31603 with broad-spectrum bactericidal activities against most of the clinically relevant pathogens. Therefore, this study aimed to statistically optimize the environmental conditions affecting ISMs production using the central composite design (CCD). Both the effect of culture media composition and incubation time and agitation rate were studied as one factor at the time (OFAT). The results showed that both the aminoglycoside production medium and the protoplast regeneration medium gave the highest specific productivity. Results also showed that 6 days incubation time and 200 rpm agitation were optimum for their production. A CCD quadratic model of 17 runs was employed to test three key variables: initial pH, incubation temperature, and concentration of calcium carbonate. A significant statistical model was obtained including, an initial pH of 6.38, incubation temperature of 30 ˚C, and 5.3% CaCO3 concentration. This model was verified experimentally in the lab and resulted in a 31-fold increase as compared to the unoptimized conditions and a threefold increase to that generated by using the optimized culture media. To our knowledge, this is the first report about studying environmental conditions affecting ISM production as OFAT and through CCD design of the response surface methodology (RSM) employed for statistical optimization. In conclusion, the CCD design is an effective tool for optimizing ISMs at the shake flask level. However, the optimized conditions generated using the CCD model in this study should be scaled up in a fermenter for industrial production of ISMs by S. tenjimariensis ATCC 31603 considering the studied environmental conditions that significantly influence the production proces.
Response Surface D-Optimal Design for Optimizing Fortimicins Production by Micromonospora olivasterospora and New Synergistic Fortimicin-A-Antibiotic Combinations

Selim HMRM, Gomaa FAM, Alshahrani MY, Aboshanab KM

Curr Microbiol, 2025 Jan 03;82(2):68.
PMID: 39753822 DOI: 10.1007/s00284-024-04049-1

Fortimicins (FTMs) are fortamine-containing aminoglycoside antibiotics (AGAs) produced by M. olivasterospora DSM 43868 with excellent bactericidal activities against a wide range of Enterobacteriaceae and synergistic activity against multidrug-resistant (MDR) pathogens. Fortimicin-A (FTM-A), the most active member of FTMs, has the lowest susceptibility to inactivation by the aminoglycoside modifying enzymes (AMEs). Therefore, this study aimed to evaluate the antibacterial activity of FTM-A alone or in combination with other antibiotics against 18 non-clonal clinically relevant MDR Gram-positive and Gram-negative pathogens. This study also aimed to statistically optimize various environmental factors affecting its production using the response surface D-optimal design. Results showed that FTM-A/meropenem combination showed the highest synergistic bactericidal activity (61.1%) followed by its combination with cefotaxime and cefepime (38.8% each). However, FTM-A/gentamicin and FTM-A/doxycycline combinations showed mostly additive effects in 66.6% and 50% of the tested isolates, respectively. For FTM-A production optimization, maximum specific activity (µg/mg) to cell growth was achieved using aminoglycoside production medium followed by yeast extract-malt extract and M65 production medium. A D-optimal quadratic model consisting of 27 different media composition variations was used to predict an optimal composition for FTM-A production and verified experimentally. Lab verification of the model was carried out using HPLC analysis, resulting in a 10.5-fold increase in their production compared to the un-optimized conditions. The model revealed that the initial pH, incubation temperature, and incubation time significantly affected FTMs production (P-value 0.05). In conclusion, the D-optimal design resulted in an effective model and optimized FTMs production on the shake flask level. FTM-A combinations with meropenem, cefotaxime, cefepime, and gentamicin showed mostly synergistic/additive effects and are advised for clinical evaluation.
Fulltext Biologically active metabolites of Alcaligenes faecalis: diversity, statistical optimization, and future perspectives

El-Sayed SE, Abdelaziz NA, Alshahrani MY, El-Housseiny GS, Aboshanab KM

Future Sci OA, 2024 Dec;10(1):2430452.
PMID: 39600180 DOI: 10.1080/20565623.2024.2430452

Alcaligenes faecalis is a Gram-negative, rod-shaped bacterium that is common in the environment and has been reported to have various bioactive metabolites of industrial potential applications, including antifungal, antibacterial, antimycobacterial, antiparasitic, anticancer, antioxidant activities. In this review, we highlighted and discussed the respective metabolites, pointing out their chemical diversities, purification, current challenges, and future directions. A. faecalis has an industrial role in biodegradation, biosurfactants, and different enzyme production. In this review, the up-to-date various Response Surface Methodology methods (RSM) that can be employed for statistical optimization of the bioactive secondary metabolites have been discussed and highlighted, pointing out the optimal use of each method, current challenges, and future directions.
Phage therapeutic delivery methods and clinical trials for combating clinically relevant pathogens

Selim HMRM, Gomaa FAM, Alshahrani MY, Morgan RN, Aboshanab KM

Ther Deliv, 2025 Mar;16(3):247-269.
PMID: 39545771 DOI: 10.1080/20415990.2024.2426824

The ongoing global health crisis caused by multidrug-resistant (MDR) bacteria necessitates quick interventions to introduce new management strategies for MDR-associated infections and antimicrobial agents' resistance. Phage therapy emerges as an antibiotic substitute for its high specificity, efficacy, and safety profiles in treating MDR-associated infections. Various in vitro and in vivo studies denoted their eminent bactericidal and anti-biofilm potential. This review addresses the latest developments in phage therapy regarding their attack strategies, formulations, and administration routes. It additionally discusses and elaborates on the status of phage therapy undergoing clinical trials, and the challenges encountered in their usage, and explores prospects in phage therapy research and application.
Evaluation of the taxonomic classification tools and visualizers for metagenomic analysis using the Oxford nanopore sequence database

Bebawy AS, Saad BT, Saad MT, Mosaad GS, Gomaa FAM, Alshahrani MY, et al.

J Appl Genet, 2025 Mar 29.
PMID: 40155586 DOI: 10.1007/s13353-025-00962-8

Microbial metagenomic identification is generally attributed to the specificity and type of the bioinformatic tools, including classifiers and visualizers. In this study, the performance of two major classifiers, Centrifuge and Kraken2, and two visualizers (Recentrifuge and Krona) has been thoroughly investigated for their efficiency in the identification of the microorganisms using the Whole-Genome Sequence (WGS) database and four targeted databases including NCBI, Silva, Greengenes, and Ribosomal Database Project (RDP). Two standard DNA metagenomic library replicates, Zymo and Zymo-1, were used as quality control. Results showed that Centrifuge gave a higher percentage of Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica identification than Kraken2. Compared to Recentrifuge, Kraken2 was more accurate in identifying Staphylococcus aureus, Listeria monocytogenes, Bacillus subtilis, and Cryptococcus neoformans. The results of the rest of the detected microorganisms were generally consistent with the two classifiers. Regarding visualizers, both Recentrifuge and Krona provided similar results regarding the abundance of each microbial species regardless of the classifier used. The differences in results between the two mentioned classifiers may be attributed to the specific algorithms each method uses and the sequencing depth. Centrifuge uses a read mapping approach, while Kraken2 uses a k-mer-based system to classify the sequencing reads into taxonomic groups. In conclusion, both Centrifuge and Kraken2 are effective tools for microbial classification. However, the choice of classifier can influence the accuracy of microbial classification and, therefore, should be made carefully, depending on the desired application, even when the same reference database is used.
Molecular detection of Candidatus Anaplasma camelii in camels (Camelus dromedarius) from Asir Province, Saudi Arabia

Alshahrani MY, Alanazi AD, Alouffi AS, Abdullah HHAM, Allam AM, Mahmoud MS, et al.

Trop Biomed, 2020 Sep 01;37(3):587-598.
PMID: 33612774 DOI: 10.47665/tb.37.3.587

Knowledge of molecular identification of tick-borne pathogens in camels in Saudi Arabia is very limited; few molecular epidemiological studies have been under taken. This study was to detect Anaplasma spp. and Piroplasma spp. in camels from Asir Province, Saudi Arabia. A total of 150 blood samples were collected from camels in Asir Province and investigated by polymerase chain reaction (PCR) that targeted 18S rRNA and 23S rRNA to detect the DNA of Piroplasma spp. and Anaplasma spp., respectively. The positive samples for 23S rRNA were assayed again by PCR targeting the 16S rRNA. All the blood samples were free from Piroplasma spp. infection. Three camels (2%) were found to be positive for Anaplasma infection through use of PCR that targeted the 23S rRNA gene. There were no significant differences between ages or sexes in the camels that tested positive for Anaplasma. All positive Anaplasma infections were recorded in camels that were infested by ticks. Two Anaplasma sequences for the16S rRNA gene were deposited in GenBank with accession numbers MN882724 and MN882725. They recorded 99.16% and 99.34% similarities (respectively) with KF843825.1 (Candidatus Anaplasma camelii reported in Unizah, Saudi Arabia). Phylogenetic analyses revealed that the two sequences recorded in this study were close to each other; both were located in one cluster with Candidatus Anaplasma camelii isolates that were recorded before in the adjacent areas of Unizah in Saudi Arabia and Iran. In conclusion: two new Anaplasma genotypes close to Candidatus Anaplasma camelii were found in camels in Asir Province, Saudi Arabia for the first time. The camels in this province were found to be free of Piroplasma infection.
Fulltext Nanomedicine-Based Drug-Targeting in Breast Cancer: Pharmacokinetics, Clinical Progress, and Challenges

Rahman M, Afzal O, Ullah SNMN, Alshahrani MY, Alkhathami AG, Altamimi ASA, et al.

ACS Omega, 2023 Dec 26;8(51):48625-48649.
PMID: 38162753 DOI: 10.1021/acsomega.3c07345

Breast cancer (BC) is a malignant neoplasm that begins in the breast tissue. After skin cancer, BC is the second most common type of cancer in women. At the end of 2040, the number of newly diagnosed BC cases is projected to increase by over 40%, reaching approximately 3 million worldwide annually. The hormonal and chemotherapeutic approaches based on conventional formulations have inappropriate therapeutic effects and suboptimal pharmacokinetic responses with nonspecific targeting actions. To overcome such issues, the use of nanomedicines, including liposomes, nanoparticles, micelles, hybrid nanoparticles, etc., has gained wider attention in the treatment of BC. Smaller dimensional nanomedicine (especially 50-200 nm) exhibited improved in vivo effectiveness, such as better tissue penetration and more effective tumor suppression through enhanced retention and permeation, as well as active targeting of the drug. Additionally, nanotechnology, which further extended and developed theranostic nanomedicine by incorporating diagnostic and imaging agents in one platform, has been applied to BC. Furthermore, hybrid and theranostic nanomedicine has also been explored for gene delivery as anticancer therapeutics in BC. Moreover, the nanocarriers' size, shape, surface charge, chemical compositions, and surface area play an important role in the nanocarriers' stability, cellular absorption, cytotoxicity, cellular uptake, and toxicity. Additionally, nanomedicine clinical translation for managing BC remains a slow process. However, a few cases are being used clinically, and their progress with the current challenges is addressed in this Review. Therefore, this Review extensively discusses recent advancements in nanomedicine and its clinical challenges in BC.