Background: Antibiotic resistance (ABR) has reached a critical level. In the near future, even the “last resort” antibiotics are likely to become ineffective against serious multidrug resistant (MDR) infections, resulting in massive morbidity and mortality. Objective: Developing a state-of-the-art update on the current situation with regard to ABR, impact of the ongoing COVID-19 pandemic on it, the preventive and control measures in progress and the solution with special reference to developing new antibiotics from new classes. Design: A review of the English medical literature with inputs from authors’ own experience. Salient Points: The growing challenge of ABR infectious diseases has further worsened since the onset of the ongoing pandemic of COVID-19. We are now fast heading towards a situation when even the “last resort” antibiotics are likely to become ineffective against the serious bateral infections. Unfortunately, researchers and innovators are still not able to develop new antibiotics from new classes. This failure is further fueling the impact of ABR crisis and posing a serious threat to our ability to successfully treat serious bacterial infections. The so-called “alternative approaches” comprising nonconventional strategies aimed at tackling MDR bugs, though in progress, are likely to provide just adjuvants rather than real substitutes for antibiotics. The hindrances in Research and Development (R&D) of new antibiotics must be handled as a top priority, clearing the way for developing newer antibiotics, not from existing classes but from brand new classes. Conclusion: The roadblocks in the endeavors aimed at developing new antibiotics from new classes need to be addressed as a top priority.