Antibiotics were our rescue team against various microbial infections, but today they’re struggling to do that. Why? Because of antimicrobial resistance, a worldwide issue that leads to poor treatment results, long hospital stays and high medical bills. 

Antimicrobial resistance (AMR) occurs when bacteria evolve and stop responding to antibiotics, making infections harder to treat.

According to the WHO report (2025), one in six laboratory-confirmed bacterial infections is now caused by a drug-resistant bacterium.^[1] Here are ten such drug-resistant superbugs that are making headlines worldwide.

Escherichia coli, a Gram-negative bacterium, is a major causative agent of urinary tract infections (UTIs) and hospital-acquired infections (HAIs). In the past, β-lactam antibiotics such as penicillins and cephalosporins were used for its treatment. But lately, resistance has been reported against this drug class due to the emergence of extended-spectrum β-lactamase (ESBL)-producing E. coli.

Resistance mechanisms include an interplay of genes, proteins, and associated enzymes:

• E. coli producing ESBL acts on the β-lactam ring of the antibiotic, which is essentially the bacteria-killing part, making it ineffective.

• ESBLs are encoded by genes such as TEM, SHV, and CTX-M.

• These genes can also be transferred to other bacteria via plasmids (extra genetic structures in bacteria) and mobile genetic elements (components promoting the movement of genetic material).

Pseudomonas aeruginosa is a Gram-negative bacterium that can thrive in diverse environments. This is also an important microbe to cause HAIs. Carbapenems are used as last-resort antibiotics against this bacterium. Today, their overuse has led to the rise of carbapenem-resistant P. aeruginosa (CRPA). 

The bacterium resists carbapenems by the following mechanisms:

• It causes changes in the oprD gene, which reduce the uptake of carbapenems into the bacterial cell.

• It increases the activity of efflux pumps, which expel the antibiotics out of the bacterium.

• It produces enzymes such as Class A and B β-lactamases, which break the β-lactam ring in the antibiotic, making it inactive.

Acinetobacter baumannii is a Gram-negative bacterium and an important agent causing HAIs, especially in ICU patients. Carbapenems are used as a last-line drug for combating this bacterium. They are now becoming ineffective due to the emergence of carbapenem-resistant A. baumannii (CRAB).

A. baumanni employs the following mechanisms to resist carbapenems:

• The bacterium produces enzymes such as Class A, B, C, and D β-lactamases, which make carbapenems inactive.

• It modifies or loses the porin proteins on its surface, which prevents antibiotics from entering.

• It alters the antibiotic-binding sites inside the cell, which prevents the drug from attaching.

• It increases the activity of efflux pumps.

Enterococci are Gram-positive bacteria normally present in the intestinal microbiota. They are also an important causative agent of HAIs, particularly in poor hygiene conditions. Vancomycin was used to treat Enterococci infections due to its broad-spectrum activity (it can kill most types of bacteria). However, its indiscriminate use has led to the emergence of vancomycin-resistant enterococci (VRE).

Enterococci resist vancomycin with the help of resistance genes, plasmids, and other related structures. These include:

• Ten types of genes that help the bacterium resist vancomycin: vanA, vanB, vanC, vanD, vanE, vanF, vanG, vanL, vanM, and vanN.

• These genes can be transferred to other bacteria through plasmids and mobile genetic elements.

Staphylococcus aureus is a Gram-positive bacterium that is normally found on our skin and in the nasal cavity. Though usually harmless, it can cause serious skin and soft tissue infections when it enters our body through cuts or breaks in the skin. MRSA was first reported in 1961 and still continues to be a high-priority pathogen according to the WHO, highlighting its significance as a superbug.^[2]

S. aureus resists methicillin through the following mechanisms:

• The presence of the mecA gene, which encodes a protein called PBP2a. This protein has a very low binding affinity for methicillin, making the drugs ineffective.

• MRSA can form biofilms (protective layers surrounding bacterial cells) that protect them from antibiotics.

Enterobacterales are Gram-negative, rod-shaped bacteria. They cause many infections in humans, such as UTIs, bloodstream infections and pneumonia. Carbapenems were frequently used to treat infections caused by Enterobacterales. However, carbapenem-resistant Enterobacterales (CRE) are now spreading at an alarming rate. Among them, Klebsiella pneumoniae (CRKP) and E. coli (CREC) account for the highest number of cases.

CRE develop resistance to carbapenems through the following mechanisms:

• They possess genes such as blaKPC, blaNDM and blaOXA-48, which code for β-lactamase enzymes.

• They decrease the permeability of their outer membrane (the outer covering of bacteria), thereby reducing antibiotic entry.

• They increase the activity of efflux pumps and alter the antibiotic binding sites.
  

Shigellosis, commonly known as dysentery, is a bacterial infection caused by Shigella species, which are Gram-negative bacteria. Most infections are caused by S. flexneri and S. sonnei. Fluoroquinolones were once an effective treatment method, but Shigella is now developing resistance to these drugs.

Shigella becomes resistant to fluoroquinolones in the following ways:

• It develops mutations (changes in its genetic material), especially in genes like gyrA, gyrB, parC, and parE.

• These changes prevent the drug from attaching properly to the bacteria, allowing it to survive the antibiotic.

Salmonella are Gram-negative bacteria broadly classified into two groups based on the disease they cause: typhoidal Salmonella and non-typhoidal Salmonella (NTS). Typhoidal Salmonella causes enteric fever, while NTS leads to intestinal infections in humans. Fluoroquinolones were once highly effective for their treatment; however, resistance has now emerged.

Salmonella resists fluoroquinolones through the following mechanisms:

• It develops mutations in gyr and par genes, resulting in lower fluoroquinolone-binding affinity.

• It carries genes that protect the bacterium from quinolones, such as qnrA, qnrB, qnrS, qnrC, and qnrD. These genes can also be transferred to other bacteria.

• It increases the activity of quinolone efflux pumps.

Gonorrhoea is a sexually transmitted infection (STI) caused by the Gram-negative bacterium N. gonorrhoeae. It spreads easily from person to person, so timely and effective treatment is essential. Cephalosporins were once highly effective against this infection, but rising antimicrobial resistance has now become a major global health concern.

N. gonorrhoeae is able to evade the action of cephalosporins via the following mechanisms:

• It can pick up resistance genes from its surroundings and add them to its own DNA. It can also receive these genes from other bacteria through plasmid transfer.

• When exposed to antibiotics, it can undergo genetic changes (mutations) that help it survive the treatment.

• It carries genes such as penA, mtrR, and penB, which produce altered proteins, increase efflux pump activity and reduce antibiotic entry.

Cephalosporins are a class of β-lactam antibiotics, categorized into five generations based on how effectively they act against bacteria. Third-generation cephalosporins have strong activity against most Enterobacterales and were commonly used to treat infections. However, Enterobacterales are showing increased resistance against this drug class, which could lead to higher rates of illness and death.

Enterobacterales resist cephalosporins through the following mechanisms:

• They produce enzymes called extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, which deactivate β-lactam antibiotics

• These genes are present in the plasmid and can be easily transferred to other bacteria.

• They alter the porin protein on their surface, reducing antibiotic entry. 

• They increase the activity of efflux pumps.

Let's recap:

Drug-resistant bacteria continue to evolve faster than the development of new antibiotics, contributing to the global rise of antimicrobial resistance. Strengthening antibiotic stewardship, improving infection control, and investing in rapid surveillance systems remain essential to slow the spread of these superbugs.

References:-

1. https://www.who.int/news/item/13-10-2025-who-warns-of-widespread-resistance-to-common-antibiotics-worldwide

2. https://iris.who.int/server/api/core/bitstreams/1a41ef7e-dd24-4ce6-a9a6-1573562e7f37/content Page 13

3. Yongqin Guo, Yangyang Hao, Mingchen Huang, Yihua Sun, Zhibo Tao,  Yang Liu, Shanshan Huang, Peng Liu, Dandan Wei. 2025. ''Whole-genome sequencing reveals resistance mechanisms and molecular epidemiology of carbapenem-resistant Pseudomonas aeruginosa bloodstream infections.'' BMC Microbiology. https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-025-04293-w

4. Joyce de Souza, Helena Regina Salomé D’Espindula, Isabel de Farias Ribeiro, Geiziane Aparecida Gonçalves, Marcelo Pillonetto, Helisson Faoro. 2025. ''Carbapenem Resistance in Acinetobacter baumannii: Mechanisms, Therapeutics, and Innovations.'' https://www.mdpi.com/2076-2607/13/7/1501

5. Dr. Sultan Ahmad, Dr. Amit Kumar Singh, Dr. Soni Sinha, Dr. Nashra Afaq, Dr. Rajesh Yadav, Dr. Rubeena Bano, Dr Nadeem Ahmad, Dr. Noor Jahan. 2025. ''Phenotypic and Molecular Characterization of ESBL-Producing Escherichia Coli in Urinary Tract Infections at a Tertiary Care Centre In India.'' International Journal of Medical and Pharmaceutical Research. https://ijmpr.in/article/phenotypic-and-molecular-characterization-of-esbl-producing-escherichia-coli-in-urinary-tract-infections-at-a-tertiary-care-centre-in-india-1099/

6. Priyanka, Kailash Jatav, Deepak Chaudhary. 2025. ''A novel real-time PCR based approach for the detection of van gene determinants in vancomycin resistant enterococci from a tertiary care hospital setting in Indore, Central India. Journal of Population Therapeutics & Clinical Pharmacology. https://jptcp.com/index.php/jptcp/article/view/10884

7. Muhammad Mubashar Idrees, Khadija Saeed, Muhammad Akbar Shahid, Muhammad Akhtar, Khadija Qammar, Javariya Hassan, Tayyaba Khaliq, Ali Saeed. 2023. ''Prevalence of mecA- and mecC-Associated Methicillin-Resistant Staphylococcus aureus in Clinical Specimens, Punjab, Pakistan. https://pmc.ncbi.nlm.nih.gov/articles/PMC10045897/#:~:text=MRSA%20strains%20harbor%20the%20mecA,has%20not%20been%20fully%20understood.

8. Hardi Patel, Aakruti Patel, Ravi Chauhan, Toral Bhavsar, Sanjay Rathod, Mina Kadam, Anurag Rawat, Seema Rawat. 2025. ''Genotypic and phenotypic characterization of virulence in methicillin resistant Staphylococcus aureus isolated from a local hospital of Ahmedabad, Gujarat, India.'' https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-025-03885-w

9. Partha Guchhait^​, Nairita Choudhuri, Bhaskar Narayan Chaudhuri, Tanni Datta^​, Arup Kumar Dawn, Pallab Das^​, Susmriti Dalui,  Satadal Das. 2025. ''Improved diagnostic stewardship in carbapenem-resistant Enterobacterales gene detection helps in early initiation of targeted therapy.'' https://www.microbiologyresearch.org/content/journal/jmm/10.1099/jmm.0.002029

10. Yan Li, Yanyan Zhang, Xinran Sun, Yuchen Wu, Zelin Yan, Xiaoyang Ju, Yonglu Huang, Hongwei Zhou, Zhiqiang Wang, Shaolin Wang, Rong Zhang, Ruichao Li. 2024. ''National genomic epidemiology investigation revealed the spread of carbapenem-resistant Escherichia coli in healthy populations and the impact on public health.'' https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01310-x?

11. Wim L. Cuypers^​, Jan Jacobs^​, Vanessa Wong, Elizabeth J. Klemm, Stijn Deborggraeve, Sandra Van Puyvelde. 2018. ''Fluoroquinolone resistance in Salmonella: insights by whole-genome sequencing.'' https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000195

12. Lindley A Barbee, Julia C Dombrowski. 2014. ''Control of Neisseria Gonorrhoeae in the Era of Evolving Antimicrobial Resistance.'' https://pmc.ncbi.nlm.nih.gov/articles/PMC3843156/#:~:text=Molecular%20mechanisms%20of%20resistance,in%20response%20to%20antibiotic%20pressure.&text=Three%20main%20resistance%20mutations%20result,result%20in%20clinically%20relevant%20resistance.

13. Chun-Lin Liu, Rui-Hang Huang, Zhi-Ying Deng, Qing- Nian Wu, Ping Chen, Zhi-Ting Huo, Jie Yao. 2025. ''A nomogram to predict bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae.'' Journal of Global Antimicrobial Resistance. https://www.sciencedirect.com/science/article/pii/S2213716525001742

Edited by M Subha Maheswari